15
Review Article Neuroprotection in Preterm Infants R. Berger and S. Söder Marienhaus Klinikum St. Elisabeth, Department of Obstetrics and Gynecology, 56564 Neuwied, Germany Correspondence should be addressed to R. Berger; [email protected] Received 14 October 2014; Accepted 22 December 2014 Academic Editor: Stefan Rimbach Copyright © 2015 R. Berger and S. S¨ oder. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preterm infants born before the 30th week of pregnancy are especially at risk of perinatal brain damage which is usually a result of cerebral ischemia or an ascending intrauterine infection. Prevention of preterm birth and early intervention given signs of imminent intrauterine infection can reduce the incidence of perinatal cerebral injury. It has been shown that administering magnesium intravenously to women at imminent risk of a preterm birth leads to a significant reduction in the likelihood of the infant developing cerebral palsy and motor skill dysfunction. It has also been demonstrated that delayed clamping of the umbilical cord aſter birth reduces the rate of brain hemorrhage among preterm infants by up to 50%. In addition, mesenchymal stem cells seem to have significant neuroprotective potential in animal experiments, as they increase the rate of regeneration of the damaged cerebral area. Clinical tests of these types of therapeutic intervention measures appear to be imminent. In the last trimester of pregnancy, the serum concentrations of estradiol and progesterone increase significantly. Preterm infants are removed abruptly from this estradiol and progesterone rich environment. It has been demonstrated in animal experiments that estradiol and progesterone protect the immature brain from hypoxic-ischemic lesions. However, this neuroprotective strategy has unfortunately not yet been subject to sufficient clinical investigation. 1. Introduction e prevention of preterm birth represents one of the most significant challenges to the field of obstetrics in the 21st cen- tury. Preterm infants born before the 30th week of pregnancy are especially at risk of prenatal mortality and morbidity [1]. Damage to the immature brain is one of the central concerns. Typical lesions include peri-/intraventricular hemorrhages (PIVH) and periventricular leukomalacia (PVL). Both of these complications specifically affect the pyramidal tracts of the lower extremities. e resulting damage leads to spastic cerebral palsy of the legs [2]. 2. Peri-Intraventricular Hemorrhage and Periventricular Leukomalacia PIVH originates in the vascular bed of the germinal matrix, an area of the brain that almost completely disappears as the fetus matures [35] (Figure 1). Blood vessels in this area of the brain burst very easily [6, 7]. Pre- and postpartal fluctuations of the cerebral blood flow can thus lead to the rupture of these blood vessels and induce PIVH [812]. e extent of the hemorrhage can be increased by an alteration in the throm- bocyte aggregation and the coagulation system [1315]. Such hemorrhages have been shown to lead to the destruction of the germinal matrix, periventricular hemorrhagic infarction of the white brain matter, and hydrocephalus [2]. PVL most commonly leads to damage of the radiatio occipitalis on the trigonum of the lateral cerebral ventricles and the white matter around the foramen of Monroe [16, 17] (Figure 2). is involves axons and oligodendrocytes, especially those that are in the early stage of development. Activated microglia then enter the lesion and strip away the necrotic tissue. Subsequently, small cysts form, which can then be identified sonographically [1820]. e lack of myelinisation as a result of damaged oligodendrocytes and an expansion of the lateral cerebral ventricle are then the consequence [2124]. PVL can be caused by both cerebral ischemia and infec- tion. During the genesis and the development of the cerebral vascular bed, vascular watersheds develop in the radiatio occipitalis on the trigonum of the lateral cerebral ventricles Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 257139, 14 pages http://dx.doi.org/10.1155/2015/257139

ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

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Page 1: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

Review ArticleNeuroprotection in Preterm Infants

R Berger and S Soumlder

Marienhaus Klinikum St Elisabeth Department of Obstetrics and Gynecology 56564 Neuwied Germany

Correspondence should be addressed to R Berger richardbergermarienhausde

Received 14 October 2014 Accepted 22 December 2014

Academic Editor Stefan Rimbach

Copyright copy 2015 R Berger and S Soder This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Preterm infants born before the 30th week of pregnancy are especially at risk of perinatal brain damage which is usually a result ofcerebral ischemia or an ascending intrauterine infection Prevention of pretermbirth and early intervention given signs of imminentintrauterine infection can reduce the incidence of perinatal cerebral injury It has been shown that administering magnesiumintravenously towomen at imminent risk of a pretermbirth leads to a significant reduction in the likelihood of the infant developingcerebral palsy and motor skill dysfunction It has also been demonstrated that delayed clamping of the umbilical cord after birthreduces the rate of brain hemorrhage among preterm infants by up to 50 In addition mesenchymal stem cells seem to havesignificant neuroprotective potential in animal experiments as they increase the rate of regeneration of the damaged cerebral areaClinical tests of these types of therapeutic intervention measures appear to be imminent In the last trimester of pregnancy theserum concentrations of estradiol and progesterone increase significantly Preterm infants are removed abruptly from this estradioland progesterone rich environment It has been demonstrated in animal experiments that estradiol and progesterone protect theimmature brain from hypoxic-ischemic lesions However this neuroprotective strategy has unfortunately not yet been subject tosufficient clinical investigation

1 Introduction

The prevention of preterm birth represents one of the mostsignificant challenges to the field of obstetrics in the 21st cen-tury Preterm infants born before the 30th week of pregnancyare especially at risk of prenatal mortality and morbidity [1]Damage to the immature brain is one of the central concernsTypical lesions include peri-intraventricular hemorrhages(PIVH) and periventricular leukomalacia (PVL) Both ofthese complications specifically affect the pyramidal tracts ofthe lower extremities The resulting damage leads to spasticcerebral palsy of the legs [2]

2 Peri-Intraventricular Hemorrhage andPeriventricular Leukomalacia

PIVH originates in the vascular bed of the germinal matrixan area of the brain that almost completely disappears as thefetusmatures [3ndash5] (Figure 1) Blood vessels in this area of thebrain burst very easily [6 7] Pre- and postpartal fluctuationsof the cerebral blood flow can thus lead to the rupture of

these blood vessels and induce PIVH [8ndash12]The extent of thehemorrhage can be increased by an alteration in the throm-bocyte aggregation and the coagulation system [13ndash15] Suchhemorrhages have been shown to lead to the destruction ofthe germinal matrix periventricular hemorrhagic infarctionof the white brain matter and hydrocephalus [2]

PVL most commonly leads to damage of the radiatiooccipitalis on the trigonum of the lateral cerebral ventriclesand the white matter around the foramen of Monroe [1617] (Figure 2) This involves axons and oligodendrocytesespecially those that are in the early stage of developmentActivated microglia then enter the lesion and strip awaythe necrotic tissue Subsequently small cysts form whichcan then be identified sonographically [18ndash20] The lack ofmyelinisation as a result of damaged oligodendrocytes andan expansion of the lateral cerebral ventricle are then theconsequence [21ndash24]

PVL can be caused by both cerebral ischemia and infec-tion During the genesis and the development of the cerebralvascular bed vascular watersheds develop in the radiatiooccipitalis on the trigonum of the lateral cerebral ventricles

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 257139 14 pageshttpdxdoiorg1011552015257139

2 BioMed Research International

GerminalmatrixTerminal

vein

Foramenof Monroe

Medullaryveins

LV

Figure 1 Germinal matrix the predilection site for peri-intraven-tricular brain hemorrhage among immature fetuses [2]

Figure 2 The left arrow marks an intraventricular hemorrhage(PIVH) The right arrow marks an area of periventricular leukoma-lacia (PVL) [25]

and the whitematter around the foramen ofMonroe [26ndash28]The vasodilatation capacity and thus the ability to increaseblood circulation during and after arterial hypotensionappear to be very restricted in these areas of the brain [29]After the 32ndweek of pregnancy the vascularisation of thesepredilection sites increases significantly and the likelihood ofPVL decreases

Ascending intrauterine infections can also induce PVL[30ndash32] An ascending infection causes a so-called ldquofetalinflammatory response syndromerdquo [33] The release of endo-toxins associated with this syndrome leads to serious imped-iment of the fetal cardiovascular system regulation resultingin a reduction in cerebral blood circulation and thus inischemic lesions in the white brainmatter [34 35] Cytokines

glutamate and free radicals are also able to directly damageoligodendrocytes in the early stages of development and thusalso disrupt the subsequent myelinisation process which cansignificantly affect the development of an infantrsquos motor skills[36ndash38] (Figure 3)

In 2000 Wu and Colford published a meta-analysisof 26 studies on the correlation between chorioamnionitisand infantile cerebral palsy [39] Their analysis showed asignificant correlation with a relative risk of 19 (95 CI14ndash25) This data was confirmed by another meta-analysispublished in 2010 [40] (Figure 4) Unfortunately it was shownthat the incidence of cerebral palsy could not be reducedby applying antibiotics as soon as chorioamnionitis hadbeen diagnosed Obviously the pathophysiological processeswhich led to the damage of the fetal brain were too advancedto be halted by means of therapeutic intervention Moreefforts should therefore be undertaken in detecting ascendingintrauterine infection very early in pregnancy Hence treat-ment of urinary tract infection by antibiotics has been shownto reduce the rate of preterm delivery [41] Unfortunatelythis effect could not be demonstrated for bacterial vaginosis[42 43]

3 Prevention of Preterm Birth and AscendingIntrauterine Infections

Due to the fact that PIVH and PVL are complicationswhich especially affect extreme preterm infants both can beavoided by preventing the baby from being born pretermMuch evidence has shown that patients who have previouslyexperienced a preterm birth or who develop shortening of thecervix to less than 25mm before the 24th week of pregnancybenefit from the prescription of progesterone [44ndash48] Thelatter group of patients should receive 200mg of progesteronedaily by vaginal suppositories whereas women with a his-tory of preterm birth can be treated either with a weeklyintramuscular application of 250mg 17-hydroxyprogesteronecaproate or by means of a daily dose of 200mg progesteroneadministered vaginally or 100mg administered orally [44ndash49] The use of a cervical cerclage in patients who have pre-viously experienced a preterm birth and develop shorteningof the cervix under 25mm before the 24th week of pregnancycan also significantly reduce the likelihood of preterm birth[50 51] Interestingly the outcome of these patients does notdiffer no matter whether they got a history indicated or asecondary cerclage However the latter procedure can helpto avoid unnecessary surgical interventions [52]

Ascending intrauterine infections which are often ob-served in patients at risk of preterm birth seem to signifi-cantly increase the risk of fetal brain damage [30] Bacterialvaginal infections should therefore be consistently treatedduring pregnancy to prevent the ascension of the infectionto the unborn child With this in mind it is very interestingto note that progesterone has anti-inflammatory proper-ties Animal experiments have demonstrated a modulatinginfluence on the gene-activation of COX-2 Connexin-43TNF-a and IL-1 beta and Toll-link receptors 2 and 4 Theproteins associated with these receptors play a central role

BioMed Research International 3

Control

80

60

40

20

0d0 d3 d6 d9

Total cell count

IFN120574 + TNF120572

lowastlowastlowast

lowastlowastlowast

(a)d3

cont

rol

d6 co

ntro

l

d9 co

ntro

l

d12

cont

rol

Actin

MBP

MAG

CNP

d3100100

d6100100

d9100100

d12100100

(b)

Figure 3 (a) Oligodendrocyte precursor cells between the 3rd and 9th day in culture (d3ndashd9) The y-axis shows the number of cells per fieldof vision The administration of INF-120574 (100UmL) and TNF-120572 (100 ngmL) severely reduced the number of surviving cells (lowastlowastlowast119875 lt 0001)Western blot was conducted for MBP MAG and CNP On the 12th day in culture pronounced expression of MBP MAG and CNP wasobserved indicating the differentiation of the oligodendrocyte precursor into the mature cell type The administration of IFN-120574 and TNF-120572almost completely inhibits the expression of these proteins [38] IFN-120574 = interferon gamma TNF-120572 = tumor necrosis factor-alpha MBP =myelin-basic protein MAG = myelin associated protein CNP = 2101584031015840-cyclic nucleotide 31015840-phosphodiesterase

Study identification Effect size (95 CI)

Redline et al (2000)

Matsuda et al [68]Gray et al (2001)Jacobsson et al (2002)

Nelson et al (2003)Wu et al (2003)Vigneswaran et al (2004)

Neufeld et al (2005)Takahashi et al (2005)

Costantine et al [74]Skrablin et al (2008)Berger et al (2009)

290 (110ndash770)

550 (150ndash2040)170 (080ndash390)180 (090ndash360)

120 (060ndash250)410 (160ndash1010)090 (050ndash160)

580 (370ndash910)090 (020ndash330)

370 (120ndash1190)270 (050ndash1730)480 (140ndash1640)241 (152ndash384)

Note weights are from random effects analysis

0049 1 204Chorioamnionitis decreased

risk of cerebral palsyChorioamnionitis increased

risk of cerebral palsy

Overall (I2 = 705 P lt 0001)

Figure 4 Meta-analysis of the association between clinical chorioamnionitis and cerebral palsy [40]

4 BioMed Research International

Table 1 Magnesium sulfate for neuroprotection

Magnesium (119873) Control (119873) RR 95 CICerebral palsy 1043052 1543093 068 (054ndash087) 119875 = 0002Gross motor skill dysfunction 572967 943013 061 (044ndash085) 119875 = 0003Infant mortality 4433052 4303093 104 (092ndash117)Antenatal administration of magnesium sulfate significantly reduced the rate of cerebral palsy and gross motor skill dysfunction among preterm infants Theinfant mortality rate remained unchanged [55]

in the induction of preterm birth [53 54] If the infectionhas reached the intrauterine environment it is necessaryto consider inducing delivery immediately to prevent anyfurther damage to the infant [39] Unfortunately we arestill lacking sound clinical parameters with which to makeadequate medical decisions in this challenging situation

4 Magnesium

If a preterm birth seems imminent the infantrsquos brain shouldbe protected by means of the intravenous application ofmagnesium [55ndash57]Within the last yearsmany experimentalstudies have been published on the neuroprotective effects ofmagnesium During acute cerebral ischemia large amountsof excitotoxic amino acids such as glutamate are releasedpresynaptically These neurotransmitters activate neuronalNMDA-receptors that operate calcium channels As a con-sequence large amounts of calcium ions flow through thesechannels down an extreme extra-intracellular concentrationgradient into the cell Excessive increase in intracellularlevels of calcium so-called calcium overload leads to celldamage through the activation of proteases lipases andendonucleases [58] Magnesium ion gates the NMDA chan-nels in a voltage-dependent manner and protects the brainfrom NMDA receptor-mediated injury [59 60] Moreovermagnesium suppresses cerebral convulsions and is a wellknown vasodilator [61 62] Both effects are known to beneuroprotective Finally magnesium has also been shown todecrease the release of nitric oxide and therefore reduce thepostischemic production of oxygen radicals [63]

Magnesium is a substance which has been used fordecades in the field of obstetrics as a prophylaxis for eclampticseizures and tocolysis In a case-control study which includedinfants weighing less than 1500 grams whose mothers weretreated with magnesium [64] the authors established thatchildren suffering from infantile cerebral palsywere less likelyto have been exposed tomagnesium sulfate than their healthymatched pairs and deduced from these findings that mag-nesium sulfate has a positive effect on very-low-birthweightinfants Several subsequent observational studies reportedsimilar findings [65ndash74] To address this open question aseries of controlled randomized studies was initiated whichincluded mothers who had been treated with MgSO

4for the

purposes of fetal neuroprotection [75ndash78]In August 2008 Rouse and colleagues published the

results of the BEAM (Beneficial Effects of Antenatal Mag-nesium Sulfate) study conducted by the Maternal-FetalMedicine Units Network [79] The primary outcome of thishigh quality study on the incidence of infantile cerebral palsy

among childrenwhosemothers had been treatedwithMgSO4

was the combined occurrence of infantile cerebral palsy (ofserious or medium severity) or death No significant differ-ence in the combined risk levels was identified between thetherapy and control groupsWhen the combined results weredisaggregated given similar mortality rates a significantlylower rate of infantile cerebral palsy was identified amongchildren whose mothers had been treated with magnesiumsulfate (19 versus 35) Rouse and colleagues concludedfrom these results that the application of MgSO

4leads to

a reduction in the incidence of cerebral palsy among verypreterm infants [79]

In 2009 a Cochrane Review was published on the topic[55] The five prospective-randomized studies it coveredwhich were published between 2002 and 2008 included atotal of 6145 children The effect of magnesium sulfate asa neuroprotective agent was tested on patients at risk ofpreterm birth before the end of the 37th week of pregnancyThe studies found a significant reduction in the incidenceof infantile cerebral palsy (relative risk 068 95 confidenceinterval 054 to 087) as well as in the incidence of grossmotor skill dysfunction (relative risk 061 95 confidenceinterval 044 to 085) among children whose mothers hadbeen treated with magnesium sulfate (Table 1) Doyle andcoworkers reevaluated the children from the ACTOMgSO

4

trial one of the five above mentioned prospective studies atschool age The effects of magnesium on the rate of cerebralpalsy and abnormalmotor function were no longer evident atthis time Possibly additional therapeutic interventions in thecontrol group may have improved the health status of thesechildren [80]

The number of women at risk of preterm birth who needto be treated with MgSO

4to prevent one case of infantile

cerebral palsy (number needed to treat (NNT)) is dependenton the week of pregnancy in which the birth occurs it is 52before the 34th week of pregnancy [81] and 29 before the 28thweek of pregnancy [82] In the USA around 2000 cases ofinfantile cerebral palsy are reported annually If all womenwho gave birth before the 34th week of pregnancy weretreatedwithmagnesium sulfate around 660 children per yearcould be spared from infantile cerebral palsy The cost ofpreventing these cases would amount to around $10291USDannually [81]

The most commonly reported maternal side-effects ofsystematic magnesium therapy include thrush sweatingnausea vomiting or skin irritation at the injection site Inaddition a 50 increase in the risk of hypotension and tachy-cardia was reported (number needed to harm (NNH) 28ndash30) A higher rate of serious complications such as maternal

BioMed Research International 5

mortality cardiac or respiratory arrest pulmonary edemarespiratory depression serious postpartal hemorrhage orincreased rate of cesarean sections was not identified

In the various studies differing amounts of magnesiumwere given to patients The levels ranged from 4 g to almost50 g of MgSO

4 A statistically significant effect was first

apparent above a moderate dosage of 4 g magnesium sulfateThere was no significant difference between the placebogroup and children whose mothers received a lower dosage[81] The total dosage of magnesium administered should betaken into consideration as controversial results reported bythe Mittendorf study are likely to be explained by the highmagnesium dosages administered (up to 500 g) [83]

The treatment should begin with a bolus injection of 4ndash6 g within 30 minutes followed by maintenance doses of 1-2 gh for 12 hours The aim of this procedure is to doublethe magnesium level in the motherrsquos serum If birth does notoccur within 12 hours the administration of magnesium canbe restarted at a later point in time if preterm birth againappears imminent

In an Australian perinatal center Ow and colleaguesinvestigated the rate of women which can be administeredmagnesium intravenously under clinical conditions for thepurpose of neuroprotection in the event of an imminentpretermbirth [84] Out of 330women at risk of pretermbirth132 were given magnesium (132330 40) A total of 74 ofall women (142191) were administered magnesium prior to apreterm birth before the 32nd week of pregnancy

The administration of high dosages of magnesium in theevent of an imminent preterm birth leads to a reductionin the rate of infantile cerebral palsy and gross motor skilldysfunction [56 85]

5 Delayed Clamping of the Umbilical Cord

An infantrsquos blood volume at birth can be significantly influ-enced by the time at which the umbilical cord is clamped [86]In 1988 Hofmeyr and colleagues published a randomizedstudy investigating the outcome among preterm infantsdependent upon the time blood flow in the umbilical cordwas interrupted [87] When the umbilical cord was clampedone minute after birth the brain hemorrhage rate was 35compared to 77 when it was clamped immediately [87]This effect is believed to be caused by the reduced risk ofhypoperfusion and improved oxygen delivery to the brain[88] Delayed clamping of the umbilical cord could also leadto an increase in the concentration of coagulation factors andin the number of stem cells which have been shown to haveneuroprotective effects in animal experiments [89 90]

Several studies published since 1980 have shown thatdelayed clamping of the umbilical cord can reduce the needfor blood and fluid transfusion as well as the rate of brainhemorrhages and sepsis among preterm infants [87 91ndash94]However delayed clamping of the umbilical cord has alsobeen associated with polycythaemia hyperbilirubinemiaand an increased need for phototherapy [91ndash94] To clarifythese issues a prospective randomized study was initiatedin 2006 Seventy-two women who experienced a preterm

birth before the 32nd week of pregnancy were divided intotwo groups in which the umbilical cord was clamped eitherearly or late (30ndash45 s after birth) A significant reduction inthe rate of brain hemorrhages and sepsis among the infantswhose umbilical cords were clamped later was observedOther variables including bilirubin and the amount of bloodtransfused were not affected [94] (Table 2) On the basis ofthis data the ACOG recommends delayed clamping of theumbilical cord among all preterm infants born before the32nd week of pregnancy [95]The infant should remain at thelevel of the placenta during this time The incidence of brainhemorrhage can thus be reduced by up to 50 It is likelythat repeated milking the umbilical cord (four times) leadsto similar results [96]

6 Experimental Approaches

In order to understand the effect of several other treatmentmeasures which have been predominantly tested in animalexperiments it is important to comprehend the pathophysi-ological processes occurring during and after an injury Theinitial damage caused by an injury is normally the result ofinsufficientmetabolic supplyThis leads to a loss ofmembranepotential a massive release of excitatory neurotransmittersand a very strong influx of calcium which in turn activatesproteases endonucleases and lipase and thus induces suc-cessive cell death [58] However significant cell damage canalso occur in the early recovery phase although oxidativephosphorylation has increased [97] Electroencephalogram isnormally suppressed and the cerebral blood flow is reducedin this phase but oxygenation of the brain usually remainswithin physiological limits [98 99] After approximately 6ndash15 hours seizures occur along with a renewed alteration ofthe mitochondrial metabolism cell edema and subsequentsecondary cerebral lesions [97 98 100] Impairment ofsubsequent neurologic development is strongly affected bythis phase [101] Such secondary damage is often followed by aphase involving tertiary damage as a result of a lack of growthfactors synaptic input and immigrating neuronal and glialstem cells [102ndash105]

7 Stem Cells

This is the point at which therapy with so-called stem cellsbecomes relevant Stem cells can be obtained from manydifferent types of tissue Depending on their origin they arereferred to as neuronal mesenchymal or hematopoietic stemcells and so forth Mesenchymal stem cells are currentlyconsidered to have themost potential for clinical applicationsThey can be grown easily from bone marrow and fromextraembryonic tissue such as the placenta Whartonrsquos jellyand umbilical cord stroma [106ndash108]

Originally it was believed that the applied stem cellsmultiplied in the damaged region where they differentiatedand replaced the destroyed tissueHowever it quickly becameclear that this could not be the way the neuroprotectivemechanism worked The low number of stem cells growingand the insufficient rate at which they differentiate in no way

6 BioMed Research International

Table 2 Neuroprotection by delayed clamping of the umbilical cord

ICC (119873 = 36)119873 () DCC (119873 = 36)119873 () 119875 Odds ratio 95 CIIVH

Total 13 (36) 5 (14) 003 35 11ndash11Grade 1 4 (11) 3 (8)Grade 2 8 (22) 2 (6)Grade 4 1 (3) 0 (0)

Sepsis 8 (22) 1 (3) 003 01 001ndash084Among infants born before the 32nd week of pregnancy delayed clamping of the umbilical cord (DCC delayed cord clamping 30ndash45 s) reduced the rate ofintraventricular brain hemorrhage (IHV) and neonatal sepsis significantly when compared to immediate severance of the cord (ICC immediate cord clamping5ndash10 s) [94]

explained the significant neuronal improvements observedRecent animal experiments have shown that the applicationof stem cells leads to a significantly improved outcome follow-ing hypoxic-ischemic damage [109ndash111]This neuroprotectiveeffect has recently also been demonstrated in preterm sheepfetuses [112] (Figure 5) The stem cells applied to damagedtissue appear to release numerous factors in the damaged areawhich induce the formation and migration of neuronal stemcells encourage the expansion of dendrites and axons andsuppress postischemic inflammation [111 113] (Figure 6)

Via transmitters mesenchymal stem cells modulatenumerous signaling cascades during apoptosis neurogenesisangiogenesis and synaptogenesis Increased expressions offibroblast growth factor-2 epidermal growth factor glial cellline-derived neurotrophic factor and sonic hedgehog havebeen observed [114] These factors play a central role in theproliferation of progenitor cells as well as in neurogenesisand cell differentiation [115ndash120] (Figure 6) Mesenchymalstem cells stimulate the proliferation of progenitor cells in thedentate gyrus These progenitor cells move into the damagedarea and differentiate under the influence of mesenchymalstem cells into astrocytes oligodendrocytes and neurons[110 121] Additionally stem cells induce the formation ofneuropilin-1 and 2 neuregulin-1 and EphrinB2 messengerswhich play an important role in the regulation of axonalgrowth synapse formation and the integration of the neu-ronal network [114 122] Mesenchymal stem cells supportthe proliferation and differentiation of oligodendrocyte-progenitor cells and thus the myelinisation of the newlyformed axons [110 123 124] Additionally mesenchymalstem cells appear to counteract glial scar formation whichhinders the migration of axons and dendrites [125 126](Figure 6)

Postischemic inflammation is most commonly causedby microglia macrophages of the central nervous systemwhich originate in bone marrow and migrate to the brainduring development where they then differentiate intomicroglia When brain damage occurs these local microgliaare activated and monocytes from peripheral blood alsomigrate to the trauma site [127 128] These so-called M1microglia release proinflammatory cytokines oxygen-basedfree radicals and neurotoxins and further damage the alteredtissue There is an alternative pathway for the activation ofmicroglia (M2) which has neuroprotective effects and leadsto the release of IL-10 insulin growth factor-1 transforming

growth factor-120573 and other immunomodulating factors [128ndash130] The application of mesenchymal stem cells reduces thenumber of classically activated microglia (M1) and thus alsoinhibits the release of proinflammatory cytokines [112 114124] In contrast theM2 cascade is activated with synthesis ofgrowth factors supporting the regeneration of damaged tissue[131 132] (Figure 6)

To what extent effects caused by mesenchymal stem cellscan also be instigated by exosomes remains to be seenExosomes are small membrane vesicles (70ndash120 nm) whichcontain lipids proteins and RNA and which are secreted byvarious types of cells Exosomes obtained frommesenchymalstem cells have been shown to reduce the extent ofmyocardialdamage following ischemia in experiments with adult mice[133]

8 Estradiol and Progesterone

The steroid hormones estradiol and progesterone play acritical role in the growth differentiation and functionof the reproductive system However the peripheral andcentral nervous system is also affected by these hormones asshown by the ubiquitous distribution of the relevant receptors[134ndash137] Estradiol induces axonal and dendritic growthand promotes the development of synapses as well as theintegration of the cerebral cortex [138]

In the third trimester of pregnancy the maternal serumconcentration of estradiol and progesterone increases sig-nificantly and can reach up to 100 times its original level[139 140] Preterm infants are removed abruptly from thisenvironment In animal experiments estradiol has beenshown to protect the immature fetal brain from hypoxic-ischemic lesions [141ndash143] (Figure 7) Progesterone has alsobeen shown to have neuroprotective effects [144] It thereforemakes sense to treat preterm infants with estradiol and pro-gesterone after birth [145] Unfortunately there is currently alack of sufficient clinical data to support such treatment [146]

The neuroprotective effects of estradiol can be impartedreceptor-dependent (genomic and nongenomic) or receptor-independent [147ndash149] The estrogen-receptor independenteffects are the result of the direct antioxidative propertiesof estradiol and of the interaction with potential bindingsites on the neuronal membrane receptors [147]These mem-brane receptors can modulate the neurotransmission andexcitability of the neuronal membrane [150 151] The classic

BioMed Research International 7

Subcortical white matter

lowastlowast

nsns

FA

030

020

010

000

Sham

SALMSC

HI

(a) (b)

(d)(c)

100502510

5

0

1005025105

0

100

0 30 60 90 120

0 30 60 90 120

50

03010 03015 03020 03025 03030 03035 03040

03010 03015 03020 03025 03030 03035 03040

0

minus50

minus100

100

50

0

minus50

minus100

Fron

tal a

EEG

Poste

rior a

EEG

(120583V

)

Fron

tal E

EG(120583

V)

(120583V

)

Poste

rior E

EG(120583

V)

lowast

nsns

SALMSC

Sham HI

Total seizure burden

Seiz

ures

(n)

500

400

300

200

100

0

Dagger

Figure 5 Hypoxic-ischemic brain damage was induced in fetal sheep on the 105th day of gestation (term is at 150 days) by occluding theumbilical cord for 25 minutes One hour after the injury had been inflicted the animals in study group were given iv 35 times 106 mesenchymalstem cells (MSCs) whereas those in the control group received saline (SAL) In sham-operated animals (Sham) occlusion was not carried out(a) Diffusion Tensor Images (DTI) measured using magnetic resonance tomography (MRI) presented as fractional anisotropy (FA) Regionsof interest SCWM (subcortical white matter) and hippocampus (b) Mesenchymal stem cells reduce brain damage in the SCWM measuredas FA Means plusmn 95 CI (lowast119875 lt 005) are depicted Dots show each measurement per animal (c) Representative image of an aEEG trace froman animal of the control group with hypoxic-ischemic brain damage The arrows mark seizures (d) The administration of MSC significantlyreduces the number of seizures (119899) (lowast119875 lt 005 Dagger119875 lt 001) [112]

receptor-mediated effects on neuronal gene transcriptioncause the growth of axons and dendrites the creation ofsynapses the expression of neurotropic factors and increasedacetylcholine synthesis In the central nervous system theestrogen receptor subtypes 120572 und 120573 have been shown to bedifferently distributed and regulated [134 135] Both receptorshave the same affinity for estradiol [152] but differing levels ofaffinity for ldquoestrogen-response-elementsrdquo and have therefore

demonstrated partially different gene activation patterns[153] Two effects of the estradiol receptor-120572 are responsiblefor the antiapoptotic propertiesThe activation of the receptorleads to a rapid induction of the insulin-like growth factor 1(IGF-1) receptor pathway and the associated signal cascade[154] IGF-1 has been shown to have neuroprotective capacity[155] In addition 17120573-estradiol inhibits the caspase-pathwaywhich plays a key role in apoptosis [156]

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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Oxidative Medicine and Cellular Longevity

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Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 2: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

2 BioMed Research International

GerminalmatrixTerminal

vein

Foramenof Monroe

Medullaryveins

LV

Figure 1 Germinal matrix the predilection site for peri-intraven-tricular brain hemorrhage among immature fetuses [2]

Figure 2 The left arrow marks an intraventricular hemorrhage(PIVH) The right arrow marks an area of periventricular leukoma-lacia (PVL) [25]

and the whitematter around the foramen ofMonroe [26ndash28]The vasodilatation capacity and thus the ability to increaseblood circulation during and after arterial hypotensionappear to be very restricted in these areas of the brain [29]After the 32ndweek of pregnancy the vascularisation of thesepredilection sites increases significantly and the likelihood ofPVL decreases

Ascending intrauterine infections can also induce PVL[30ndash32] An ascending infection causes a so-called ldquofetalinflammatory response syndromerdquo [33] The release of endo-toxins associated with this syndrome leads to serious imped-iment of the fetal cardiovascular system regulation resultingin a reduction in cerebral blood circulation and thus inischemic lesions in the white brainmatter [34 35] Cytokines

glutamate and free radicals are also able to directly damageoligodendrocytes in the early stages of development and thusalso disrupt the subsequent myelinisation process which cansignificantly affect the development of an infantrsquos motor skills[36ndash38] (Figure 3)

In 2000 Wu and Colford published a meta-analysisof 26 studies on the correlation between chorioamnionitisand infantile cerebral palsy [39] Their analysis showed asignificant correlation with a relative risk of 19 (95 CI14ndash25) This data was confirmed by another meta-analysispublished in 2010 [40] (Figure 4) Unfortunately it was shownthat the incidence of cerebral palsy could not be reducedby applying antibiotics as soon as chorioamnionitis hadbeen diagnosed Obviously the pathophysiological processeswhich led to the damage of the fetal brain were too advancedto be halted by means of therapeutic intervention Moreefforts should therefore be undertaken in detecting ascendingintrauterine infection very early in pregnancy Hence treat-ment of urinary tract infection by antibiotics has been shownto reduce the rate of preterm delivery [41] Unfortunatelythis effect could not be demonstrated for bacterial vaginosis[42 43]

3 Prevention of Preterm Birth and AscendingIntrauterine Infections

Due to the fact that PIVH and PVL are complicationswhich especially affect extreme preterm infants both can beavoided by preventing the baby from being born pretermMuch evidence has shown that patients who have previouslyexperienced a preterm birth or who develop shortening of thecervix to less than 25mm before the 24th week of pregnancybenefit from the prescription of progesterone [44ndash48] Thelatter group of patients should receive 200mg of progesteronedaily by vaginal suppositories whereas women with a his-tory of preterm birth can be treated either with a weeklyintramuscular application of 250mg 17-hydroxyprogesteronecaproate or by means of a daily dose of 200mg progesteroneadministered vaginally or 100mg administered orally [44ndash49] The use of a cervical cerclage in patients who have pre-viously experienced a preterm birth and develop shorteningof the cervix under 25mm before the 24th week of pregnancycan also significantly reduce the likelihood of preterm birth[50 51] Interestingly the outcome of these patients does notdiffer no matter whether they got a history indicated or asecondary cerclage However the latter procedure can helpto avoid unnecessary surgical interventions [52]

Ascending intrauterine infections which are often ob-served in patients at risk of preterm birth seem to signifi-cantly increase the risk of fetal brain damage [30] Bacterialvaginal infections should therefore be consistently treatedduring pregnancy to prevent the ascension of the infectionto the unborn child With this in mind it is very interestingto note that progesterone has anti-inflammatory proper-ties Animal experiments have demonstrated a modulatinginfluence on the gene-activation of COX-2 Connexin-43TNF-a and IL-1 beta and Toll-link receptors 2 and 4 Theproteins associated with these receptors play a central role

BioMed Research International 3

Control

80

60

40

20

0d0 d3 d6 d9

Total cell count

IFN120574 + TNF120572

lowastlowastlowast

lowastlowastlowast

(a)d3

cont

rol

d6 co

ntro

l

d9 co

ntro

l

d12

cont

rol

Actin

MBP

MAG

CNP

d3100100

d6100100

d9100100

d12100100

(b)

Figure 3 (a) Oligodendrocyte precursor cells between the 3rd and 9th day in culture (d3ndashd9) The y-axis shows the number of cells per fieldof vision The administration of INF-120574 (100UmL) and TNF-120572 (100 ngmL) severely reduced the number of surviving cells (lowastlowastlowast119875 lt 0001)Western blot was conducted for MBP MAG and CNP On the 12th day in culture pronounced expression of MBP MAG and CNP wasobserved indicating the differentiation of the oligodendrocyte precursor into the mature cell type The administration of IFN-120574 and TNF-120572almost completely inhibits the expression of these proteins [38] IFN-120574 = interferon gamma TNF-120572 = tumor necrosis factor-alpha MBP =myelin-basic protein MAG = myelin associated protein CNP = 2101584031015840-cyclic nucleotide 31015840-phosphodiesterase

Study identification Effect size (95 CI)

Redline et al (2000)

Matsuda et al [68]Gray et al (2001)Jacobsson et al (2002)

Nelson et al (2003)Wu et al (2003)Vigneswaran et al (2004)

Neufeld et al (2005)Takahashi et al (2005)

Costantine et al [74]Skrablin et al (2008)Berger et al (2009)

290 (110ndash770)

550 (150ndash2040)170 (080ndash390)180 (090ndash360)

120 (060ndash250)410 (160ndash1010)090 (050ndash160)

580 (370ndash910)090 (020ndash330)

370 (120ndash1190)270 (050ndash1730)480 (140ndash1640)241 (152ndash384)

Note weights are from random effects analysis

0049 1 204Chorioamnionitis decreased

risk of cerebral palsyChorioamnionitis increased

risk of cerebral palsy

Overall (I2 = 705 P lt 0001)

Figure 4 Meta-analysis of the association between clinical chorioamnionitis and cerebral palsy [40]

4 BioMed Research International

Table 1 Magnesium sulfate for neuroprotection

Magnesium (119873) Control (119873) RR 95 CICerebral palsy 1043052 1543093 068 (054ndash087) 119875 = 0002Gross motor skill dysfunction 572967 943013 061 (044ndash085) 119875 = 0003Infant mortality 4433052 4303093 104 (092ndash117)Antenatal administration of magnesium sulfate significantly reduced the rate of cerebral palsy and gross motor skill dysfunction among preterm infants Theinfant mortality rate remained unchanged [55]

in the induction of preterm birth [53 54] If the infectionhas reached the intrauterine environment it is necessaryto consider inducing delivery immediately to prevent anyfurther damage to the infant [39] Unfortunately we arestill lacking sound clinical parameters with which to makeadequate medical decisions in this challenging situation

4 Magnesium

If a preterm birth seems imminent the infantrsquos brain shouldbe protected by means of the intravenous application ofmagnesium [55ndash57]Within the last yearsmany experimentalstudies have been published on the neuroprotective effects ofmagnesium During acute cerebral ischemia large amountsof excitotoxic amino acids such as glutamate are releasedpresynaptically These neurotransmitters activate neuronalNMDA-receptors that operate calcium channels As a con-sequence large amounts of calcium ions flow through thesechannels down an extreme extra-intracellular concentrationgradient into the cell Excessive increase in intracellularlevels of calcium so-called calcium overload leads to celldamage through the activation of proteases lipases andendonucleases [58] Magnesium ion gates the NMDA chan-nels in a voltage-dependent manner and protects the brainfrom NMDA receptor-mediated injury [59 60] Moreovermagnesium suppresses cerebral convulsions and is a wellknown vasodilator [61 62] Both effects are known to beneuroprotective Finally magnesium has also been shown todecrease the release of nitric oxide and therefore reduce thepostischemic production of oxygen radicals [63]

Magnesium is a substance which has been used fordecades in the field of obstetrics as a prophylaxis for eclampticseizures and tocolysis In a case-control study which includedinfants weighing less than 1500 grams whose mothers weretreated with magnesium [64] the authors established thatchildren suffering from infantile cerebral palsywere less likelyto have been exposed tomagnesium sulfate than their healthymatched pairs and deduced from these findings that mag-nesium sulfate has a positive effect on very-low-birthweightinfants Several subsequent observational studies reportedsimilar findings [65ndash74] To address this open question aseries of controlled randomized studies was initiated whichincluded mothers who had been treated with MgSO

4for the

purposes of fetal neuroprotection [75ndash78]In August 2008 Rouse and colleagues published the

results of the BEAM (Beneficial Effects of Antenatal Mag-nesium Sulfate) study conducted by the Maternal-FetalMedicine Units Network [79] The primary outcome of thishigh quality study on the incidence of infantile cerebral palsy

among childrenwhosemothers had been treatedwithMgSO4

was the combined occurrence of infantile cerebral palsy (ofserious or medium severity) or death No significant differ-ence in the combined risk levels was identified between thetherapy and control groupsWhen the combined results weredisaggregated given similar mortality rates a significantlylower rate of infantile cerebral palsy was identified amongchildren whose mothers had been treated with magnesiumsulfate (19 versus 35) Rouse and colleagues concludedfrom these results that the application of MgSO

4leads to

a reduction in the incidence of cerebral palsy among verypreterm infants [79]

In 2009 a Cochrane Review was published on the topic[55] The five prospective-randomized studies it coveredwhich were published between 2002 and 2008 included atotal of 6145 children The effect of magnesium sulfate asa neuroprotective agent was tested on patients at risk ofpreterm birth before the end of the 37th week of pregnancyThe studies found a significant reduction in the incidenceof infantile cerebral palsy (relative risk 068 95 confidenceinterval 054 to 087) as well as in the incidence of grossmotor skill dysfunction (relative risk 061 95 confidenceinterval 044 to 085) among children whose mothers hadbeen treated with magnesium sulfate (Table 1) Doyle andcoworkers reevaluated the children from the ACTOMgSO

4

trial one of the five above mentioned prospective studies atschool age The effects of magnesium on the rate of cerebralpalsy and abnormalmotor function were no longer evident atthis time Possibly additional therapeutic interventions in thecontrol group may have improved the health status of thesechildren [80]

The number of women at risk of preterm birth who needto be treated with MgSO

4to prevent one case of infantile

cerebral palsy (number needed to treat (NNT)) is dependenton the week of pregnancy in which the birth occurs it is 52before the 34th week of pregnancy [81] and 29 before the 28thweek of pregnancy [82] In the USA around 2000 cases ofinfantile cerebral palsy are reported annually If all womenwho gave birth before the 34th week of pregnancy weretreatedwithmagnesium sulfate around 660 children per yearcould be spared from infantile cerebral palsy The cost ofpreventing these cases would amount to around $10291USDannually [81]

The most commonly reported maternal side-effects ofsystematic magnesium therapy include thrush sweatingnausea vomiting or skin irritation at the injection site Inaddition a 50 increase in the risk of hypotension and tachy-cardia was reported (number needed to harm (NNH) 28ndash30) A higher rate of serious complications such as maternal

BioMed Research International 5

mortality cardiac or respiratory arrest pulmonary edemarespiratory depression serious postpartal hemorrhage orincreased rate of cesarean sections was not identified

In the various studies differing amounts of magnesiumwere given to patients The levels ranged from 4 g to almost50 g of MgSO

4 A statistically significant effect was first

apparent above a moderate dosage of 4 g magnesium sulfateThere was no significant difference between the placebogroup and children whose mothers received a lower dosage[81] The total dosage of magnesium administered should betaken into consideration as controversial results reported bythe Mittendorf study are likely to be explained by the highmagnesium dosages administered (up to 500 g) [83]

The treatment should begin with a bolus injection of 4ndash6 g within 30 minutes followed by maintenance doses of 1-2 gh for 12 hours The aim of this procedure is to doublethe magnesium level in the motherrsquos serum If birth does notoccur within 12 hours the administration of magnesium canbe restarted at a later point in time if preterm birth againappears imminent

In an Australian perinatal center Ow and colleaguesinvestigated the rate of women which can be administeredmagnesium intravenously under clinical conditions for thepurpose of neuroprotection in the event of an imminentpretermbirth [84] Out of 330women at risk of pretermbirth132 were given magnesium (132330 40) A total of 74 ofall women (142191) were administered magnesium prior to apreterm birth before the 32nd week of pregnancy

The administration of high dosages of magnesium in theevent of an imminent preterm birth leads to a reductionin the rate of infantile cerebral palsy and gross motor skilldysfunction [56 85]

5 Delayed Clamping of the Umbilical Cord

An infantrsquos blood volume at birth can be significantly influ-enced by the time at which the umbilical cord is clamped [86]In 1988 Hofmeyr and colleagues published a randomizedstudy investigating the outcome among preterm infantsdependent upon the time blood flow in the umbilical cordwas interrupted [87] When the umbilical cord was clampedone minute after birth the brain hemorrhage rate was 35compared to 77 when it was clamped immediately [87]This effect is believed to be caused by the reduced risk ofhypoperfusion and improved oxygen delivery to the brain[88] Delayed clamping of the umbilical cord could also leadto an increase in the concentration of coagulation factors andin the number of stem cells which have been shown to haveneuroprotective effects in animal experiments [89 90]

Several studies published since 1980 have shown thatdelayed clamping of the umbilical cord can reduce the needfor blood and fluid transfusion as well as the rate of brainhemorrhages and sepsis among preterm infants [87 91ndash94]However delayed clamping of the umbilical cord has alsobeen associated with polycythaemia hyperbilirubinemiaand an increased need for phototherapy [91ndash94] To clarifythese issues a prospective randomized study was initiatedin 2006 Seventy-two women who experienced a preterm

birth before the 32nd week of pregnancy were divided intotwo groups in which the umbilical cord was clamped eitherearly or late (30ndash45 s after birth) A significant reduction inthe rate of brain hemorrhages and sepsis among the infantswhose umbilical cords were clamped later was observedOther variables including bilirubin and the amount of bloodtransfused were not affected [94] (Table 2) On the basis ofthis data the ACOG recommends delayed clamping of theumbilical cord among all preterm infants born before the32nd week of pregnancy [95]The infant should remain at thelevel of the placenta during this time The incidence of brainhemorrhage can thus be reduced by up to 50 It is likelythat repeated milking the umbilical cord (four times) leadsto similar results [96]

6 Experimental Approaches

In order to understand the effect of several other treatmentmeasures which have been predominantly tested in animalexperiments it is important to comprehend the pathophysi-ological processes occurring during and after an injury Theinitial damage caused by an injury is normally the result ofinsufficientmetabolic supplyThis leads to a loss ofmembranepotential a massive release of excitatory neurotransmittersand a very strong influx of calcium which in turn activatesproteases endonucleases and lipase and thus induces suc-cessive cell death [58] However significant cell damage canalso occur in the early recovery phase although oxidativephosphorylation has increased [97] Electroencephalogram isnormally suppressed and the cerebral blood flow is reducedin this phase but oxygenation of the brain usually remainswithin physiological limits [98 99] After approximately 6ndash15 hours seizures occur along with a renewed alteration ofthe mitochondrial metabolism cell edema and subsequentsecondary cerebral lesions [97 98 100] Impairment ofsubsequent neurologic development is strongly affected bythis phase [101] Such secondary damage is often followed by aphase involving tertiary damage as a result of a lack of growthfactors synaptic input and immigrating neuronal and glialstem cells [102ndash105]

7 Stem Cells

This is the point at which therapy with so-called stem cellsbecomes relevant Stem cells can be obtained from manydifferent types of tissue Depending on their origin they arereferred to as neuronal mesenchymal or hematopoietic stemcells and so forth Mesenchymal stem cells are currentlyconsidered to have themost potential for clinical applicationsThey can be grown easily from bone marrow and fromextraembryonic tissue such as the placenta Whartonrsquos jellyand umbilical cord stroma [106ndash108]

Originally it was believed that the applied stem cellsmultiplied in the damaged region where they differentiatedand replaced the destroyed tissueHowever it quickly becameclear that this could not be the way the neuroprotectivemechanism worked The low number of stem cells growingand the insufficient rate at which they differentiate in no way

6 BioMed Research International

Table 2 Neuroprotection by delayed clamping of the umbilical cord

ICC (119873 = 36)119873 () DCC (119873 = 36)119873 () 119875 Odds ratio 95 CIIVH

Total 13 (36) 5 (14) 003 35 11ndash11Grade 1 4 (11) 3 (8)Grade 2 8 (22) 2 (6)Grade 4 1 (3) 0 (0)

Sepsis 8 (22) 1 (3) 003 01 001ndash084Among infants born before the 32nd week of pregnancy delayed clamping of the umbilical cord (DCC delayed cord clamping 30ndash45 s) reduced the rate ofintraventricular brain hemorrhage (IHV) and neonatal sepsis significantly when compared to immediate severance of the cord (ICC immediate cord clamping5ndash10 s) [94]

explained the significant neuronal improvements observedRecent animal experiments have shown that the applicationof stem cells leads to a significantly improved outcome follow-ing hypoxic-ischemic damage [109ndash111]This neuroprotectiveeffect has recently also been demonstrated in preterm sheepfetuses [112] (Figure 5) The stem cells applied to damagedtissue appear to release numerous factors in the damaged areawhich induce the formation and migration of neuronal stemcells encourage the expansion of dendrites and axons andsuppress postischemic inflammation [111 113] (Figure 6)

Via transmitters mesenchymal stem cells modulatenumerous signaling cascades during apoptosis neurogenesisangiogenesis and synaptogenesis Increased expressions offibroblast growth factor-2 epidermal growth factor glial cellline-derived neurotrophic factor and sonic hedgehog havebeen observed [114] These factors play a central role in theproliferation of progenitor cells as well as in neurogenesisand cell differentiation [115ndash120] (Figure 6) Mesenchymalstem cells stimulate the proliferation of progenitor cells in thedentate gyrus These progenitor cells move into the damagedarea and differentiate under the influence of mesenchymalstem cells into astrocytes oligodendrocytes and neurons[110 121] Additionally stem cells induce the formation ofneuropilin-1 and 2 neuregulin-1 and EphrinB2 messengerswhich play an important role in the regulation of axonalgrowth synapse formation and the integration of the neu-ronal network [114 122] Mesenchymal stem cells supportthe proliferation and differentiation of oligodendrocyte-progenitor cells and thus the myelinisation of the newlyformed axons [110 123 124] Additionally mesenchymalstem cells appear to counteract glial scar formation whichhinders the migration of axons and dendrites [125 126](Figure 6)

Postischemic inflammation is most commonly causedby microglia macrophages of the central nervous systemwhich originate in bone marrow and migrate to the brainduring development where they then differentiate intomicroglia When brain damage occurs these local microgliaare activated and monocytes from peripheral blood alsomigrate to the trauma site [127 128] These so-called M1microglia release proinflammatory cytokines oxygen-basedfree radicals and neurotoxins and further damage the alteredtissue There is an alternative pathway for the activation ofmicroglia (M2) which has neuroprotective effects and leadsto the release of IL-10 insulin growth factor-1 transforming

growth factor-120573 and other immunomodulating factors [128ndash130] The application of mesenchymal stem cells reduces thenumber of classically activated microglia (M1) and thus alsoinhibits the release of proinflammatory cytokines [112 114124] In contrast theM2 cascade is activated with synthesis ofgrowth factors supporting the regeneration of damaged tissue[131 132] (Figure 6)

To what extent effects caused by mesenchymal stem cellscan also be instigated by exosomes remains to be seenExosomes are small membrane vesicles (70ndash120 nm) whichcontain lipids proteins and RNA and which are secreted byvarious types of cells Exosomes obtained frommesenchymalstem cells have been shown to reduce the extent ofmyocardialdamage following ischemia in experiments with adult mice[133]

8 Estradiol and Progesterone

The steroid hormones estradiol and progesterone play acritical role in the growth differentiation and functionof the reproductive system However the peripheral andcentral nervous system is also affected by these hormones asshown by the ubiquitous distribution of the relevant receptors[134ndash137] Estradiol induces axonal and dendritic growthand promotes the development of synapses as well as theintegration of the cerebral cortex [138]

In the third trimester of pregnancy the maternal serumconcentration of estradiol and progesterone increases sig-nificantly and can reach up to 100 times its original level[139 140] Preterm infants are removed abruptly from thisenvironment In animal experiments estradiol has beenshown to protect the immature fetal brain from hypoxic-ischemic lesions [141ndash143] (Figure 7) Progesterone has alsobeen shown to have neuroprotective effects [144] It thereforemakes sense to treat preterm infants with estradiol and pro-gesterone after birth [145] Unfortunately there is currently alack of sufficient clinical data to support such treatment [146]

The neuroprotective effects of estradiol can be impartedreceptor-dependent (genomic and nongenomic) or receptor-independent [147ndash149] The estrogen-receptor independenteffects are the result of the direct antioxidative propertiesof estradiol and of the interaction with potential bindingsites on the neuronal membrane receptors [147]These mem-brane receptors can modulate the neurotransmission andexcitability of the neuronal membrane [150 151] The classic

BioMed Research International 7

Subcortical white matter

lowastlowast

nsns

FA

030

020

010

000

Sham

SALMSC

HI

(a) (b)

(d)(c)

100502510

5

0

1005025105

0

100

0 30 60 90 120

0 30 60 90 120

50

03010 03015 03020 03025 03030 03035 03040

03010 03015 03020 03025 03030 03035 03040

0

minus50

minus100

100

50

0

minus50

minus100

Fron

tal a

EEG

Poste

rior a

EEG

(120583V

)

Fron

tal E

EG(120583

V)

(120583V

)

Poste

rior E

EG(120583

V)

lowast

nsns

SALMSC

Sham HI

Total seizure burden

Seiz

ures

(n)

500

400

300

200

100

0

Dagger

Figure 5 Hypoxic-ischemic brain damage was induced in fetal sheep on the 105th day of gestation (term is at 150 days) by occluding theumbilical cord for 25 minutes One hour after the injury had been inflicted the animals in study group were given iv 35 times 106 mesenchymalstem cells (MSCs) whereas those in the control group received saline (SAL) In sham-operated animals (Sham) occlusion was not carried out(a) Diffusion Tensor Images (DTI) measured using magnetic resonance tomography (MRI) presented as fractional anisotropy (FA) Regionsof interest SCWM (subcortical white matter) and hippocampus (b) Mesenchymal stem cells reduce brain damage in the SCWM measuredas FA Means plusmn 95 CI (lowast119875 lt 005) are depicted Dots show each measurement per animal (c) Representative image of an aEEG trace froman animal of the control group with hypoxic-ischemic brain damage The arrows mark seizures (d) The administration of MSC significantlyreduces the number of seizures (119899) (lowast119875 lt 005 Dagger119875 lt 001) [112]

receptor-mediated effects on neuronal gene transcriptioncause the growth of axons and dendrites the creation ofsynapses the expression of neurotropic factors and increasedacetylcholine synthesis In the central nervous system theestrogen receptor subtypes 120572 und 120573 have been shown to bedifferently distributed and regulated [134 135] Both receptorshave the same affinity for estradiol [152] but differing levels ofaffinity for ldquoestrogen-response-elementsrdquo and have therefore

demonstrated partially different gene activation patterns[153] Two effects of the estradiol receptor-120572 are responsiblefor the antiapoptotic propertiesThe activation of the receptorleads to a rapid induction of the insulin-like growth factor 1(IGF-1) receptor pathway and the associated signal cascade[154] IGF-1 has been shown to have neuroprotective capacity[155] In addition 17120573-estradiol inhibits the caspase-pathwaywhich plays a key role in apoptosis [156]

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Disease Markers

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 3: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

BioMed Research International 3

Control

80

60

40

20

0d0 d3 d6 d9

Total cell count

IFN120574 + TNF120572

lowastlowastlowast

lowastlowastlowast

(a)d3

cont

rol

d6 co

ntro

l

d9 co

ntro

l

d12

cont

rol

Actin

MBP

MAG

CNP

d3100100

d6100100

d9100100

d12100100

(b)

Figure 3 (a) Oligodendrocyte precursor cells between the 3rd and 9th day in culture (d3ndashd9) The y-axis shows the number of cells per fieldof vision The administration of INF-120574 (100UmL) and TNF-120572 (100 ngmL) severely reduced the number of surviving cells (lowastlowastlowast119875 lt 0001)Western blot was conducted for MBP MAG and CNP On the 12th day in culture pronounced expression of MBP MAG and CNP wasobserved indicating the differentiation of the oligodendrocyte precursor into the mature cell type The administration of IFN-120574 and TNF-120572almost completely inhibits the expression of these proteins [38] IFN-120574 = interferon gamma TNF-120572 = tumor necrosis factor-alpha MBP =myelin-basic protein MAG = myelin associated protein CNP = 2101584031015840-cyclic nucleotide 31015840-phosphodiesterase

Study identification Effect size (95 CI)

Redline et al (2000)

Matsuda et al [68]Gray et al (2001)Jacobsson et al (2002)

Nelson et al (2003)Wu et al (2003)Vigneswaran et al (2004)

Neufeld et al (2005)Takahashi et al (2005)

Costantine et al [74]Skrablin et al (2008)Berger et al (2009)

290 (110ndash770)

550 (150ndash2040)170 (080ndash390)180 (090ndash360)

120 (060ndash250)410 (160ndash1010)090 (050ndash160)

580 (370ndash910)090 (020ndash330)

370 (120ndash1190)270 (050ndash1730)480 (140ndash1640)241 (152ndash384)

Note weights are from random effects analysis

0049 1 204Chorioamnionitis decreased

risk of cerebral palsyChorioamnionitis increased

risk of cerebral palsy

Overall (I2 = 705 P lt 0001)

Figure 4 Meta-analysis of the association between clinical chorioamnionitis and cerebral palsy [40]

4 BioMed Research International

Table 1 Magnesium sulfate for neuroprotection

Magnesium (119873) Control (119873) RR 95 CICerebral palsy 1043052 1543093 068 (054ndash087) 119875 = 0002Gross motor skill dysfunction 572967 943013 061 (044ndash085) 119875 = 0003Infant mortality 4433052 4303093 104 (092ndash117)Antenatal administration of magnesium sulfate significantly reduced the rate of cerebral palsy and gross motor skill dysfunction among preterm infants Theinfant mortality rate remained unchanged [55]

in the induction of preterm birth [53 54] If the infectionhas reached the intrauterine environment it is necessaryto consider inducing delivery immediately to prevent anyfurther damage to the infant [39] Unfortunately we arestill lacking sound clinical parameters with which to makeadequate medical decisions in this challenging situation

4 Magnesium

If a preterm birth seems imminent the infantrsquos brain shouldbe protected by means of the intravenous application ofmagnesium [55ndash57]Within the last yearsmany experimentalstudies have been published on the neuroprotective effects ofmagnesium During acute cerebral ischemia large amountsof excitotoxic amino acids such as glutamate are releasedpresynaptically These neurotransmitters activate neuronalNMDA-receptors that operate calcium channels As a con-sequence large amounts of calcium ions flow through thesechannels down an extreme extra-intracellular concentrationgradient into the cell Excessive increase in intracellularlevels of calcium so-called calcium overload leads to celldamage through the activation of proteases lipases andendonucleases [58] Magnesium ion gates the NMDA chan-nels in a voltage-dependent manner and protects the brainfrom NMDA receptor-mediated injury [59 60] Moreovermagnesium suppresses cerebral convulsions and is a wellknown vasodilator [61 62] Both effects are known to beneuroprotective Finally magnesium has also been shown todecrease the release of nitric oxide and therefore reduce thepostischemic production of oxygen radicals [63]

Magnesium is a substance which has been used fordecades in the field of obstetrics as a prophylaxis for eclampticseizures and tocolysis In a case-control study which includedinfants weighing less than 1500 grams whose mothers weretreated with magnesium [64] the authors established thatchildren suffering from infantile cerebral palsywere less likelyto have been exposed tomagnesium sulfate than their healthymatched pairs and deduced from these findings that mag-nesium sulfate has a positive effect on very-low-birthweightinfants Several subsequent observational studies reportedsimilar findings [65ndash74] To address this open question aseries of controlled randomized studies was initiated whichincluded mothers who had been treated with MgSO

4for the

purposes of fetal neuroprotection [75ndash78]In August 2008 Rouse and colleagues published the

results of the BEAM (Beneficial Effects of Antenatal Mag-nesium Sulfate) study conducted by the Maternal-FetalMedicine Units Network [79] The primary outcome of thishigh quality study on the incidence of infantile cerebral palsy

among childrenwhosemothers had been treatedwithMgSO4

was the combined occurrence of infantile cerebral palsy (ofserious or medium severity) or death No significant differ-ence in the combined risk levels was identified between thetherapy and control groupsWhen the combined results weredisaggregated given similar mortality rates a significantlylower rate of infantile cerebral palsy was identified amongchildren whose mothers had been treated with magnesiumsulfate (19 versus 35) Rouse and colleagues concludedfrom these results that the application of MgSO

4leads to

a reduction in the incidence of cerebral palsy among verypreterm infants [79]

In 2009 a Cochrane Review was published on the topic[55] The five prospective-randomized studies it coveredwhich were published between 2002 and 2008 included atotal of 6145 children The effect of magnesium sulfate asa neuroprotective agent was tested on patients at risk ofpreterm birth before the end of the 37th week of pregnancyThe studies found a significant reduction in the incidenceof infantile cerebral palsy (relative risk 068 95 confidenceinterval 054 to 087) as well as in the incidence of grossmotor skill dysfunction (relative risk 061 95 confidenceinterval 044 to 085) among children whose mothers hadbeen treated with magnesium sulfate (Table 1) Doyle andcoworkers reevaluated the children from the ACTOMgSO

4

trial one of the five above mentioned prospective studies atschool age The effects of magnesium on the rate of cerebralpalsy and abnormalmotor function were no longer evident atthis time Possibly additional therapeutic interventions in thecontrol group may have improved the health status of thesechildren [80]

The number of women at risk of preterm birth who needto be treated with MgSO

4to prevent one case of infantile

cerebral palsy (number needed to treat (NNT)) is dependenton the week of pregnancy in which the birth occurs it is 52before the 34th week of pregnancy [81] and 29 before the 28thweek of pregnancy [82] In the USA around 2000 cases ofinfantile cerebral palsy are reported annually If all womenwho gave birth before the 34th week of pregnancy weretreatedwithmagnesium sulfate around 660 children per yearcould be spared from infantile cerebral palsy The cost ofpreventing these cases would amount to around $10291USDannually [81]

The most commonly reported maternal side-effects ofsystematic magnesium therapy include thrush sweatingnausea vomiting or skin irritation at the injection site Inaddition a 50 increase in the risk of hypotension and tachy-cardia was reported (number needed to harm (NNH) 28ndash30) A higher rate of serious complications such as maternal

BioMed Research International 5

mortality cardiac or respiratory arrest pulmonary edemarespiratory depression serious postpartal hemorrhage orincreased rate of cesarean sections was not identified

In the various studies differing amounts of magnesiumwere given to patients The levels ranged from 4 g to almost50 g of MgSO

4 A statistically significant effect was first

apparent above a moderate dosage of 4 g magnesium sulfateThere was no significant difference between the placebogroup and children whose mothers received a lower dosage[81] The total dosage of magnesium administered should betaken into consideration as controversial results reported bythe Mittendorf study are likely to be explained by the highmagnesium dosages administered (up to 500 g) [83]

The treatment should begin with a bolus injection of 4ndash6 g within 30 minutes followed by maintenance doses of 1-2 gh for 12 hours The aim of this procedure is to doublethe magnesium level in the motherrsquos serum If birth does notoccur within 12 hours the administration of magnesium canbe restarted at a later point in time if preterm birth againappears imminent

In an Australian perinatal center Ow and colleaguesinvestigated the rate of women which can be administeredmagnesium intravenously under clinical conditions for thepurpose of neuroprotection in the event of an imminentpretermbirth [84] Out of 330women at risk of pretermbirth132 were given magnesium (132330 40) A total of 74 ofall women (142191) were administered magnesium prior to apreterm birth before the 32nd week of pregnancy

The administration of high dosages of magnesium in theevent of an imminent preterm birth leads to a reductionin the rate of infantile cerebral palsy and gross motor skilldysfunction [56 85]

5 Delayed Clamping of the Umbilical Cord

An infantrsquos blood volume at birth can be significantly influ-enced by the time at which the umbilical cord is clamped [86]In 1988 Hofmeyr and colleagues published a randomizedstudy investigating the outcome among preterm infantsdependent upon the time blood flow in the umbilical cordwas interrupted [87] When the umbilical cord was clampedone minute after birth the brain hemorrhage rate was 35compared to 77 when it was clamped immediately [87]This effect is believed to be caused by the reduced risk ofhypoperfusion and improved oxygen delivery to the brain[88] Delayed clamping of the umbilical cord could also leadto an increase in the concentration of coagulation factors andin the number of stem cells which have been shown to haveneuroprotective effects in animal experiments [89 90]

Several studies published since 1980 have shown thatdelayed clamping of the umbilical cord can reduce the needfor blood and fluid transfusion as well as the rate of brainhemorrhages and sepsis among preterm infants [87 91ndash94]However delayed clamping of the umbilical cord has alsobeen associated with polycythaemia hyperbilirubinemiaand an increased need for phototherapy [91ndash94] To clarifythese issues a prospective randomized study was initiatedin 2006 Seventy-two women who experienced a preterm

birth before the 32nd week of pregnancy were divided intotwo groups in which the umbilical cord was clamped eitherearly or late (30ndash45 s after birth) A significant reduction inthe rate of brain hemorrhages and sepsis among the infantswhose umbilical cords were clamped later was observedOther variables including bilirubin and the amount of bloodtransfused were not affected [94] (Table 2) On the basis ofthis data the ACOG recommends delayed clamping of theumbilical cord among all preterm infants born before the32nd week of pregnancy [95]The infant should remain at thelevel of the placenta during this time The incidence of brainhemorrhage can thus be reduced by up to 50 It is likelythat repeated milking the umbilical cord (four times) leadsto similar results [96]

6 Experimental Approaches

In order to understand the effect of several other treatmentmeasures which have been predominantly tested in animalexperiments it is important to comprehend the pathophysi-ological processes occurring during and after an injury Theinitial damage caused by an injury is normally the result ofinsufficientmetabolic supplyThis leads to a loss ofmembranepotential a massive release of excitatory neurotransmittersand a very strong influx of calcium which in turn activatesproteases endonucleases and lipase and thus induces suc-cessive cell death [58] However significant cell damage canalso occur in the early recovery phase although oxidativephosphorylation has increased [97] Electroencephalogram isnormally suppressed and the cerebral blood flow is reducedin this phase but oxygenation of the brain usually remainswithin physiological limits [98 99] After approximately 6ndash15 hours seizures occur along with a renewed alteration ofthe mitochondrial metabolism cell edema and subsequentsecondary cerebral lesions [97 98 100] Impairment ofsubsequent neurologic development is strongly affected bythis phase [101] Such secondary damage is often followed by aphase involving tertiary damage as a result of a lack of growthfactors synaptic input and immigrating neuronal and glialstem cells [102ndash105]

7 Stem Cells

This is the point at which therapy with so-called stem cellsbecomes relevant Stem cells can be obtained from manydifferent types of tissue Depending on their origin they arereferred to as neuronal mesenchymal or hematopoietic stemcells and so forth Mesenchymal stem cells are currentlyconsidered to have themost potential for clinical applicationsThey can be grown easily from bone marrow and fromextraembryonic tissue such as the placenta Whartonrsquos jellyand umbilical cord stroma [106ndash108]

Originally it was believed that the applied stem cellsmultiplied in the damaged region where they differentiatedand replaced the destroyed tissueHowever it quickly becameclear that this could not be the way the neuroprotectivemechanism worked The low number of stem cells growingand the insufficient rate at which they differentiate in no way

6 BioMed Research International

Table 2 Neuroprotection by delayed clamping of the umbilical cord

ICC (119873 = 36)119873 () DCC (119873 = 36)119873 () 119875 Odds ratio 95 CIIVH

Total 13 (36) 5 (14) 003 35 11ndash11Grade 1 4 (11) 3 (8)Grade 2 8 (22) 2 (6)Grade 4 1 (3) 0 (0)

Sepsis 8 (22) 1 (3) 003 01 001ndash084Among infants born before the 32nd week of pregnancy delayed clamping of the umbilical cord (DCC delayed cord clamping 30ndash45 s) reduced the rate ofintraventricular brain hemorrhage (IHV) and neonatal sepsis significantly when compared to immediate severance of the cord (ICC immediate cord clamping5ndash10 s) [94]

explained the significant neuronal improvements observedRecent animal experiments have shown that the applicationof stem cells leads to a significantly improved outcome follow-ing hypoxic-ischemic damage [109ndash111]This neuroprotectiveeffect has recently also been demonstrated in preterm sheepfetuses [112] (Figure 5) The stem cells applied to damagedtissue appear to release numerous factors in the damaged areawhich induce the formation and migration of neuronal stemcells encourage the expansion of dendrites and axons andsuppress postischemic inflammation [111 113] (Figure 6)

Via transmitters mesenchymal stem cells modulatenumerous signaling cascades during apoptosis neurogenesisangiogenesis and synaptogenesis Increased expressions offibroblast growth factor-2 epidermal growth factor glial cellline-derived neurotrophic factor and sonic hedgehog havebeen observed [114] These factors play a central role in theproliferation of progenitor cells as well as in neurogenesisand cell differentiation [115ndash120] (Figure 6) Mesenchymalstem cells stimulate the proliferation of progenitor cells in thedentate gyrus These progenitor cells move into the damagedarea and differentiate under the influence of mesenchymalstem cells into astrocytes oligodendrocytes and neurons[110 121] Additionally stem cells induce the formation ofneuropilin-1 and 2 neuregulin-1 and EphrinB2 messengerswhich play an important role in the regulation of axonalgrowth synapse formation and the integration of the neu-ronal network [114 122] Mesenchymal stem cells supportthe proliferation and differentiation of oligodendrocyte-progenitor cells and thus the myelinisation of the newlyformed axons [110 123 124] Additionally mesenchymalstem cells appear to counteract glial scar formation whichhinders the migration of axons and dendrites [125 126](Figure 6)

Postischemic inflammation is most commonly causedby microglia macrophages of the central nervous systemwhich originate in bone marrow and migrate to the brainduring development where they then differentiate intomicroglia When brain damage occurs these local microgliaare activated and monocytes from peripheral blood alsomigrate to the trauma site [127 128] These so-called M1microglia release proinflammatory cytokines oxygen-basedfree radicals and neurotoxins and further damage the alteredtissue There is an alternative pathway for the activation ofmicroglia (M2) which has neuroprotective effects and leadsto the release of IL-10 insulin growth factor-1 transforming

growth factor-120573 and other immunomodulating factors [128ndash130] The application of mesenchymal stem cells reduces thenumber of classically activated microglia (M1) and thus alsoinhibits the release of proinflammatory cytokines [112 114124] In contrast theM2 cascade is activated with synthesis ofgrowth factors supporting the regeneration of damaged tissue[131 132] (Figure 6)

To what extent effects caused by mesenchymal stem cellscan also be instigated by exosomes remains to be seenExosomes are small membrane vesicles (70ndash120 nm) whichcontain lipids proteins and RNA and which are secreted byvarious types of cells Exosomes obtained frommesenchymalstem cells have been shown to reduce the extent ofmyocardialdamage following ischemia in experiments with adult mice[133]

8 Estradiol and Progesterone

The steroid hormones estradiol and progesterone play acritical role in the growth differentiation and functionof the reproductive system However the peripheral andcentral nervous system is also affected by these hormones asshown by the ubiquitous distribution of the relevant receptors[134ndash137] Estradiol induces axonal and dendritic growthand promotes the development of synapses as well as theintegration of the cerebral cortex [138]

In the third trimester of pregnancy the maternal serumconcentration of estradiol and progesterone increases sig-nificantly and can reach up to 100 times its original level[139 140] Preterm infants are removed abruptly from thisenvironment In animal experiments estradiol has beenshown to protect the immature fetal brain from hypoxic-ischemic lesions [141ndash143] (Figure 7) Progesterone has alsobeen shown to have neuroprotective effects [144] It thereforemakes sense to treat preterm infants with estradiol and pro-gesterone after birth [145] Unfortunately there is currently alack of sufficient clinical data to support such treatment [146]

The neuroprotective effects of estradiol can be impartedreceptor-dependent (genomic and nongenomic) or receptor-independent [147ndash149] The estrogen-receptor independenteffects are the result of the direct antioxidative propertiesof estradiol and of the interaction with potential bindingsites on the neuronal membrane receptors [147]These mem-brane receptors can modulate the neurotransmission andexcitability of the neuronal membrane [150 151] The classic

BioMed Research International 7

Subcortical white matter

lowastlowast

nsns

FA

030

020

010

000

Sham

SALMSC

HI

(a) (b)

(d)(c)

100502510

5

0

1005025105

0

100

0 30 60 90 120

0 30 60 90 120

50

03010 03015 03020 03025 03030 03035 03040

03010 03015 03020 03025 03030 03035 03040

0

minus50

minus100

100

50

0

minus50

minus100

Fron

tal a

EEG

Poste

rior a

EEG

(120583V

)

Fron

tal E

EG(120583

V)

(120583V

)

Poste

rior E

EG(120583

V)

lowast

nsns

SALMSC

Sham HI

Total seizure burden

Seiz

ures

(n)

500

400

300

200

100

0

Dagger

Figure 5 Hypoxic-ischemic brain damage was induced in fetal sheep on the 105th day of gestation (term is at 150 days) by occluding theumbilical cord for 25 minutes One hour after the injury had been inflicted the animals in study group were given iv 35 times 106 mesenchymalstem cells (MSCs) whereas those in the control group received saline (SAL) In sham-operated animals (Sham) occlusion was not carried out(a) Diffusion Tensor Images (DTI) measured using magnetic resonance tomography (MRI) presented as fractional anisotropy (FA) Regionsof interest SCWM (subcortical white matter) and hippocampus (b) Mesenchymal stem cells reduce brain damage in the SCWM measuredas FA Means plusmn 95 CI (lowast119875 lt 005) are depicted Dots show each measurement per animal (c) Representative image of an aEEG trace froman animal of the control group with hypoxic-ischemic brain damage The arrows mark seizures (d) The administration of MSC significantlyreduces the number of seizures (119899) (lowast119875 lt 005 Dagger119875 lt 001) [112]

receptor-mediated effects on neuronal gene transcriptioncause the growth of axons and dendrites the creation ofsynapses the expression of neurotropic factors and increasedacetylcholine synthesis In the central nervous system theestrogen receptor subtypes 120572 und 120573 have been shown to bedifferently distributed and regulated [134 135] Both receptorshave the same affinity for estradiol [152] but differing levels ofaffinity for ldquoestrogen-response-elementsrdquo and have therefore

demonstrated partially different gene activation patterns[153] Two effects of the estradiol receptor-120572 are responsiblefor the antiapoptotic propertiesThe activation of the receptorleads to a rapid induction of the insulin-like growth factor 1(IGF-1) receptor pathway and the associated signal cascade[154] IGF-1 has been shown to have neuroprotective capacity[155] In addition 17120573-estradiol inhibits the caspase-pathwaywhich plays a key role in apoptosis [156]

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Page 4: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

4 BioMed Research International

Table 1 Magnesium sulfate for neuroprotection

Magnesium (119873) Control (119873) RR 95 CICerebral palsy 1043052 1543093 068 (054ndash087) 119875 = 0002Gross motor skill dysfunction 572967 943013 061 (044ndash085) 119875 = 0003Infant mortality 4433052 4303093 104 (092ndash117)Antenatal administration of magnesium sulfate significantly reduced the rate of cerebral palsy and gross motor skill dysfunction among preterm infants Theinfant mortality rate remained unchanged [55]

in the induction of preterm birth [53 54] If the infectionhas reached the intrauterine environment it is necessaryto consider inducing delivery immediately to prevent anyfurther damage to the infant [39] Unfortunately we arestill lacking sound clinical parameters with which to makeadequate medical decisions in this challenging situation

4 Magnesium

If a preterm birth seems imminent the infantrsquos brain shouldbe protected by means of the intravenous application ofmagnesium [55ndash57]Within the last yearsmany experimentalstudies have been published on the neuroprotective effects ofmagnesium During acute cerebral ischemia large amountsof excitotoxic amino acids such as glutamate are releasedpresynaptically These neurotransmitters activate neuronalNMDA-receptors that operate calcium channels As a con-sequence large amounts of calcium ions flow through thesechannels down an extreme extra-intracellular concentrationgradient into the cell Excessive increase in intracellularlevels of calcium so-called calcium overload leads to celldamage through the activation of proteases lipases andendonucleases [58] Magnesium ion gates the NMDA chan-nels in a voltage-dependent manner and protects the brainfrom NMDA receptor-mediated injury [59 60] Moreovermagnesium suppresses cerebral convulsions and is a wellknown vasodilator [61 62] Both effects are known to beneuroprotective Finally magnesium has also been shown todecrease the release of nitric oxide and therefore reduce thepostischemic production of oxygen radicals [63]

Magnesium is a substance which has been used fordecades in the field of obstetrics as a prophylaxis for eclampticseizures and tocolysis In a case-control study which includedinfants weighing less than 1500 grams whose mothers weretreated with magnesium [64] the authors established thatchildren suffering from infantile cerebral palsywere less likelyto have been exposed tomagnesium sulfate than their healthymatched pairs and deduced from these findings that mag-nesium sulfate has a positive effect on very-low-birthweightinfants Several subsequent observational studies reportedsimilar findings [65ndash74] To address this open question aseries of controlled randomized studies was initiated whichincluded mothers who had been treated with MgSO

4for the

purposes of fetal neuroprotection [75ndash78]In August 2008 Rouse and colleagues published the

results of the BEAM (Beneficial Effects of Antenatal Mag-nesium Sulfate) study conducted by the Maternal-FetalMedicine Units Network [79] The primary outcome of thishigh quality study on the incidence of infantile cerebral palsy

among childrenwhosemothers had been treatedwithMgSO4

was the combined occurrence of infantile cerebral palsy (ofserious or medium severity) or death No significant differ-ence in the combined risk levels was identified between thetherapy and control groupsWhen the combined results weredisaggregated given similar mortality rates a significantlylower rate of infantile cerebral palsy was identified amongchildren whose mothers had been treated with magnesiumsulfate (19 versus 35) Rouse and colleagues concludedfrom these results that the application of MgSO

4leads to

a reduction in the incidence of cerebral palsy among verypreterm infants [79]

In 2009 a Cochrane Review was published on the topic[55] The five prospective-randomized studies it coveredwhich were published between 2002 and 2008 included atotal of 6145 children The effect of magnesium sulfate asa neuroprotective agent was tested on patients at risk ofpreterm birth before the end of the 37th week of pregnancyThe studies found a significant reduction in the incidenceof infantile cerebral palsy (relative risk 068 95 confidenceinterval 054 to 087) as well as in the incidence of grossmotor skill dysfunction (relative risk 061 95 confidenceinterval 044 to 085) among children whose mothers hadbeen treated with magnesium sulfate (Table 1) Doyle andcoworkers reevaluated the children from the ACTOMgSO

4

trial one of the five above mentioned prospective studies atschool age The effects of magnesium on the rate of cerebralpalsy and abnormalmotor function were no longer evident atthis time Possibly additional therapeutic interventions in thecontrol group may have improved the health status of thesechildren [80]

The number of women at risk of preterm birth who needto be treated with MgSO

4to prevent one case of infantile

cerebral palsy (number needed to treat (NNT)) is dependenton the week of pregnancy in which the birth occurs it is 52before the 34th week of pregnancy [81] and 29 before the 28thweek of pregnancy [82] In the USA around 2000 cases ofinfantile cerebral palsy are reported annually If all womenwho gave birth before the 34th week of pregnancy weretreatedwithmagnesium sulfate around 660 children per yearcould be spared from infantile cerebral palsy The cost ofpreventing these cases would amount to around $10291USDannually [81]

The most commonly reported maternal side-effects ofsystematic magnesium therapy include thrush sweatingnausea vomiting or skin irritation at the injection site Inaddition a 50 increase in the risk of hypotension and tachy-cardia was reported (number needed to harm (NNH) 28ndash30) A higher rate of serious complications such as maternal

BioMed Research International 5

mortality cardiac or respiratory arrest pulmonary edemarespiratory depression serious postpartal hemorrhage orincreased rate of cesarean sections was not identified

In the various studies differing amounts of magnesiumwere given to patients The levels ranged from 4 g to almost50 g of MgSO

4 A statistically significant effect was first

apparent above a moderate dosage of 4 g magnesium sulfateThere was no significant difference between the placebogroup and children whose mothers received a lower dosage[81] The total dosage of magnesium administered should betaken into consideration as controversial results reported bythe Mittendorf study are likely to be explained by the highmagnesium dosages administered (up to 500 g) [83]

The treatment should begin with a bolus injection of 4ndash6 g within 30 minutes followed by maintenance doses of 1-2 gh for 12 hours The aim of this procedure is to doublethe magnesium level in the motherrsquos serum If birth does notoccur within 12 hours the administration of magnesium canbe restarted at a later point in time if preterm birth againappears imminent

In an Australian perinatal center Ow and colleaguesinvestigated the rate of women which can be administeredmagnesium intravenously under clinical conditions for thepurpose of neuroprotection in the event of an imminentpretermbirth [84] Out of 330women at risk of pretermbirth132 were given magnesium (132330 40) A total of 74 ofall women (142191) were administered magnesium prior to apreterm birth before the 32nd week of pregnancy

The administration of high dosages of magnesium in theevent of an imminent preterm birth leads to a reductionin the rate of infantile cerebral palsy and gross motor skilldysfunction [56 85]

5 Delayed Clamping of the Umbilical Cord

An infantrsquos blood volume at birth can be significantly influ-enced by the time at which the umbilical cord is clamped [86]In 1988 Hofmeyr and colleagues published a randomizedstudy investigating the outcome among preterm infantsdependent upon the time blood flow in the umbilical cordwas interrupted [87] When the umbilical cord was clampedone minute after birth the brain hemorrhage rate was 35compared to 77 when it was clamped immediately [87]This effect is believed to be caused by the reduced risk ofhypoperfusion and improved oxygen delivery to the brain[88] Delayed clamping of the umbilical cord could also leadto an increase in the concentration of coagulation factors andin the number of stem cells which have been shown to haveneuroprotective effects in animal experiments [89 90]

Several studies published since 1980 have shown thatdelayed clamping of the umbilical cord can reduce the needfor blood and fluid transfusion as well as the rate of brainhemorrhages and sepsis among preterm infants [87 91ndash94]However delayed clamping of the umbilical cord has alsobeen associated with polycythaemia hyperbilirubinemiaand an increased need for phototherapy [91ndash94] To clarifythese issues a prospective randomized study was initiatedin 2006 Seventy-two women who experienced a preterm

birth before the 32nd week of pregnancy were divided intotwo groups in which the umbilical cord was clamped eitherearly or late (30ndash45 s after birth) A significant reduction inthe rate of brain hemorrhages and sepsis among the infantswhose umbilical cords were clamped later was observedOther variables including bilirubin and the amount of bloodtransfused were not affected [94] (Table 2) On the basis ofthis data the ACOG recommends delayed clamping of theumbilical cord among all preterm infants born before the32nd week of pregnancy [95]The infant should remain at thelevel of the placenta during this time The incidence of brainhemorrhage can thus be reduced by up to 50 It is likelythat repeated milking the umbilical cord (four times) leadsto similar results [96]

6 Experimental Approaches

In order to understand the effect of several other treatmentmeasures which have been predominantly tested in animalexperiments it is important to comprehend the pathophysi-ological processes occurring during and after an injury Theinitial damage caused by an injury is normally the result ofinsufficientmetabolic supplyThis leads to a loss ofmembranepotential a massive release of excitatory neurotransmittersand a very strong influx of calcium which in turn activatesproteases endonucleases and lipase and thus induces suc-cessive cell death [58] However significant cell damage canalso occur in the early recovery phase although oxidativephosphorylation has increased [97] Electroencephalogram isnormally suppressed and the cerebral blood flow is reducedin this phase but oxygenation of the brain usually remainswithin physiological limits [98 99] After approximately 6ndash15 hours seizures occur along with a renewed alteration ofthe mitochondrial metabolism cell edema and subsequentsecondary cerebral lesions [97 98 100] Impairment ofsubsequent neurologic development is strongly affected bythis phase [101] Such secondary damage is often followed by aphase involving tertiary damage as a result of a lack of growthfactors synaptic input and immigrating neuronal and glialstem cells [102ndash105]

7 Stem Cells

This is the point at which therapy with so-called stem cellsbecomes relevant Stem cells can be obtained from manydifferent types of tissue Depending on their origin they arereferred to as neuronal mesenchymal or hematopoietic stemcells and so forth Mesenchymal stem cells are currentlyconsidered to have themost potential for clinical applicationsThey can be grown easily from bone marrow and fromextraembryonic tissue such as the placenta Whartonrsquos jellyand umbilical cord stroma [106ndash108]

Originally it was believed that the applied stem cellsmultiplied in the damaged region where they differentiatedand replaced the destroyed tissueHowever it quickly becameclear that this could not be the way the neuroprotectivemechanism worked The low number of stem cells growingand the insufficient rate at which they differentiate in no way

6 BioMed Research International

Table 2 Neuroprotection by delayed clamping of the umbilical cord

ICC (119873 = 36)119873 () DCC (119873 = 36)119873 () 119875 Odds ratio 95 CIIVH

Total 13 (36) 5 (14) 003 35 11ndash11Grade 1 4 (11) 3 (8)Grade 2 8 (22) 2 (6)Grade 4 1 (3) 0 (0)

Sepsis 8 (22) 1 (3) 003 01 001ndash084Among infants born before the 32nd week of pregnancy delayed clamping of the umbilical cord (DCC delayed cord clamping 30ndash45 s) reduced the rate ofintraventricular brain hemorrhage (IHV) and neonatal sepsis significantly when compared to immediate severance of the cord (ICC immediate cord clamping5ndash10 s) [94]

explained the significant neuronal improvements observedRecent animal experiments have shown that the applicationof stem cells leads to a significantly improved outcome follow-ing hypoxic-ischemic damage [109ndash111]This neuroprotectiveeffect has recently also been demonstrated in preterm sheepfetuses [112] (Figure 5) The stem cells applied to damagedtissue appear to release numerous factors in the damaged areawhich induce the formation and migration of neuronal stemcells encourage the expansion of dendrites and axons andsuppress postischemic inflammation [111 113] (Figure 6)

Via transmitters mesenchymal stem cells modulatenumerous signaling cascades during apoptosis neurogenesisangiogenesis and synaptogenesis Increased expressions offibroblast growth factor-2 epidermal growth factor glial cellline-derived neurotrophic factor and sonic hedgehog havebeen observed [114] These factors play a central role in theproliferation of progenitor cells as well as in neurogenesisand cell differentiation [115ndash120] (Figure 6) Mesenchymalstem cells stimulate the proliferation of progenitor cells in thedentate gyrus These progenitor cells move into the damagedarea and differentiate under the influence of mesenchymalstem cells into astrocytes oligodendrocytes and neurons[110 121] Additionally stem cells induce the formation ofneuropilin-1 and 2 neuregulin-1 and EphrinB2 messengerswhich play an important role in the regulation of axonalgrowth synapse formation and the integration of the neu-ronal network [114 122] Mesenchymal stem cells supportthe proliferation and differentiation of oligodendrocyte-progenitor cells and thus the myelinisation of the newlyformed axons [110 123 124] Additionally mesenchymalstem cells appear to counteract glial scar formation whichhinders the migration of axons and dendrites [125 126](Figure 6)

Postischemic inflammation is most commonly causedby microglia macrophages of the central nervous systemwhich originate in bone marrow and migrate to the brainduring development where they then differentiate intomicroglia When brain damage occurs these local microgliaare activated and monocytes from peripheral blood alsomigrate to the trauma site [127 128] These so-called M1microglia release proinflammatory cytokines oxygen-basedfree radicals and neurotoxins and further damage the alteredtissue There is an alternative pathway for the activation ofmicroglia (M2) which has neuroprotective effects and leadsto the release of IL-10 insulin growth factor-1 transforming

growth factor-120573 and other immunomodulating factors [128ndash130] The application of mesenchymal stem cells reduces thenumber of classically activated microglia (M1) and thus alsoinhibits the release of proinflammatory cytokines [112 114124] In contrast theM2 cascade is activated with synthesis ofgrowth factors supporting the regeneration of damaged tissue[131 132] (Figure 6)

To what extent effects caused by mesenchymal stem cellscan also be instigated by exosomes remains to be seenExosomes are small membrane vesicles (70ndash120 nm) whichcontain lipids proteins and RNA and which are secreted byvarious types of cells Exosomes obtained frommesenchymalstem cells have been shown to reduce the extent ofmyocardialdamage following ischemia in experiments with adult mice[133]

8 Estradiol and Progesterone

The steroid hormones estradiol and progesterone play acritical role in the growth differentiation and functionof the reproductive system However the peripheral andcentral nervous system is also affected by these hormones asshown by the ubiquitous distribution of the relevant receptors[134ndash137] Estradiol induces axonal and dendritic growthand promotes the development of synapses as well as theintegration of the cerebral cortex [138]

In the third trimester of pregnancy the maternal serumconcentration of estradiol and progesterone increases sig-nificantly and can reach up to 100 times its original level[139 140] Preterm infants are removed abruptly from thisenvironment In animal experiments estradiol has beenshown to protect the immature fetal brain from hypoxic-ischemic lesions [141ndash143] (Figure 7) Progesterone has alsobeen shown to have neuroprotective effects [144] It thereforemakes sense to treat preterm infants with estradiol and pro-gesterone after birth [145] Unfortunately there is currently alack of sufficient clinical data to support such treatment [146]

The neuroprotective effects of estradiol can be impartedreceptor-dependent (genomic and nongenomic) or receptor-independent [147ndash149] The estrogen-receptor independenteffects are the result of the direct antioxidative propertiesof estradiol and of the interaction with potential bindingsites on the neuronal membrane receptors [147]These mem-brane receptors can modulate the neurotransmission andexcitability of the neuronal membrane [150 151] The classic

BioMed Research International 7

Subcortical white matter

lowastlowast

nsns

FA

030

020

010

000

Sham

SALMSC

HI

(a) (b)

(d)(c)

100502510

5

0

1005025105

0

100

0 30 60 90 120

0 30 60 90 120

50

03010 03015 03020 03025 03030 03035 03040

03010 03015 03020 03025 03030 03035 03040

0

minus50

minus100

100

50

0

minus50

minus100

Fron

tal a

EEG

Poste

rior a

EEG

(120583V

)

Fron

tal E

EG(120583

V)

(120583V

)

Poste

rior E

EG(120583

V)

lowast

nsns

SALMSC

Sham HI

Total seizure burden

Seiz

ures

(n)

500

400

300

200

100

0

Dagger

Figure 5 Hypoxic-ischemic brain damage was induced in fetal sheep on the 105th day of gestation (term is at 150 days) by occluding theumbilical cord for 25 minutes One hour after the injury had been inflicted the animals in study group were given iv 35 times 106 mesenchymalstem cells (MSCs) whereas those in the control group received saline (SAL) In sham-operated animals (Sham) occlusion was not carried out(a) Diffusion Tensor Images (DTI) measured using magnetic resonance tomography (MRI) presented as fractional anisotropy (FA) Regionsof interest SCWM (subcortical white matter) and hippocampus (b) Mesenchymal stem cells reduce brain damage in the SCWM measuredas FA Means plusmn 95 CI (lowast119875 lt 005) are depicted Dots show each measurement per animal (c) Representative image of an aEEG trace froman animal of the control group with hypoxic-ischemic brain damage The arrows mark seizures (d) The administration of MSC significantlyreduces the number of seizures (119899) (lowast119875 lt 005 Dagger119875 lt 001) [112]

receptor-mediated effects on neuronal gene transcriptioncause the growth of axons and dendrites the creation ofsynapses the expression of neurotropic factors and increasedacetylcholine synthesis In the central nervous system theestrogen receptor subtypes 120572 und 120573 have been shown to bedifferently distributed and regulated [134 135] Both receptorshave the same affinity for estradiol [152] but differing levels ofaffinity for ldquoestrogen-response-elementsrdquo and have therefore

demonstrated partially different gene activation patterns[153] Two effects of the estradiol receptor-120572 are responsiblefor the antiapoptotic propertiesThe activation of the receptorleads to a rapid induction of the insulin-like growth factor 1(IGF-1) receptor pathway and the associated signal cascade[154] IGF-1 has been shown to have neuroprotective capacity[155] In addition 17120573-estradiol inhibits the caspase-pathwaywhich plays a key role in apoptosis [156]

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 5: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

BioMed Research International 5

mortality cardiac or respiratory arrest pulmonary edemarespiratory depression serious postpartal hemorrhage orincreased rate of cesarean sections was not identified

In the various studies differing amounts of magnesiumwere given to patients The levels ranged from 4 g to almost50 g of MgSO

4 A statistically significant effect was first

apparent above a moderate dosage of 4 g magnesium sulfateThere was no significant difference between the placebogroup and children whose mothers received a lower dosage[81] The total dosage of magnesium administered should betaken into consideration as controversial results reported bythe Mittendorf study are likely to be explained by the highmagnesium dosages administered (up to 500 g) [83]

The treatment should begin with a bolus injection of 4ndash6 g within 30 minutes followed by maintenance doses of 1-2 gh for 12 hours The aim of this procedure is to doublethe magnesium level in the motherrsquos serum If birth does notoccur within 12 hours the administration of magnesium canbe restarted at a later point in time if preterm birth againappears imminent

In an Australian perinatal center Ow and colleaguesinvestigated the rate of women which can be administeredmagnesium intravenously under clinical conditions for thepurpose of neuroprotection in the event of an imminentpretermbirth [84] Out of 330women at risk of pretermbirth132 were given magnesium (132330 40) A total of 74 ofall women (142191) were administered magnesium prior to apreterm birth before the 32nd week of pregnancy

The administration of high dosages of magnesium in theevent of an imminent preterm birth leads to a reductionin the rate of infantile cerebral palsy and gross motor skilldysfunction [56 85]

5 Delayed Clamping of the Umbilical Cord

An infantrsquos blood volume at birth can be significantly influ-enced by the time at which the umbilical cord is clamped [86]In 1988 Hofmeyr and colleagues published a randomizedstudy investigating the outcome among preterm infantsdependent upon the time blood flow in the umbilical cordwas interrupted [87] When the umbilical cord was clampedone minute after birth the brain hemorrhage rate was 35compared to 77 when it was clamped immediately [87]This effect is believed to be caused by the reduced risk ofhypoperfusion and improved oxygen delivery to the brain[88] Delayed clamping of the umbilical cord could also leadto an increase in the concentration of coagulation factors andin the number of stem cells which have been shown to haveneuroprotective effects in animal experiments [89 90]

Several studies published since 1980 have shown thatdelayed clamping of the umbilical cord can reduce the needfor blood and fluid transfusion as well as the rate of brainhemorrhages and sepsis among preterm infants [87 91ndash94]However delayed clamping of the umbilical cord has alsobeen associated with polycythaemia hyperbilirubinemiaand an increased need for phototherapy [91ndash94] To clarifythese issues a prospective randomized study was initiatedin 2006 Seventy-two women who experienced a preterm

birth before the 32nd week of pregnancy were divided intotwo groups in which the umbilical cord was clamped eitherearly or late (30ndash45 s after birth) A significant reduction inthe rate of brain hemorrhages and sepsis among the infantswhose umbilical cords were clamped later was observedOther variables including bilirubin and the amount of bloodtransfused were not affected [94] (Table 2) On the basis ofthis data the ACOG recommends delayed clamping of theumbilical cord among all preterm infants born before the32nd week of pregnancy [95]The infant should remain at thelevel of the placenta during this time The incidence of brainhemorrhage can thus be reduced by up to 50 It is likelythat repeated milking the umbilical cord (four times) leadsto similar results [96]

6 Experimental Approaches

In order to understand the effect of several other treatmentmeasures which have been predominantly tested in animalexperiments it is important to comprehend the pathophysi-ological processes occurring during and after an injury Theinitial damage caused by an injury is normally the result ofinsufficientmetabolic supplyThis leads to a loss ofmembranepotential a massive release of excitatory neurotransmittersand a very strong influx of calcium which in turn activatesproteases endonucleases and lipase and thus induces suc-cessive cell death [58] However significant cell damage canalso occur in the early recovery phase although oxidativephosphorylation has increased [97] Electroencephalogram isnormally suppressed and the cerebral blood flow is reducedin this phase but oxygenation of the brain usually remainswithin physiological limits [98 99] After approximately 6ndash15 hours seizures occur along with a renewed alteration ofthe mitochondrial metabolism cell edema and subsequentsecondary cerebral lesions [97 98 100] Impairment ofsubsequent neurologic development is strongly affected bythis phase [101] Such secondary damage is often followed by aphase involving tertiary damage as a result of a lack of growthfactors synaptic input and immigrating neuronal and glialstem cells [102ndash105]

7 Stem Cells

This is the point at which therapy with so-called stem cellsbecomes relevant Stem cells can be obtained from manydifferent types of tissue Depending on their origin they arereferred to as neuronal mesenchymal or hematopoietic stemcells and so forth Mesenchymal stem cells are currentlyconsidered to have themost potential for clinical applicationsThey can be grown easily from bone marrow and fromextraembryonic tissue such as the placenta Whartonrsquos jellyand umbilical cord stroma [106ndash108]

Originally it was believed that the applied stem cellsmultiplied in the damaged region where they differentiatedand replaced the destroyed tissueHowever it quickly becameclear that this could not be the way the neuroprotectivemechanism worked The low number of stem cells growingand the insufficient rate at which they differentiate in no way

6 BioMed Research International

Table 2 Neuroprotection by delayed clamping of the umbilical cord

ICC (119873 = 36)119873 () DCC (119873 = 36)119873 () 119875 Odds ratio 95 CIIVH

Total 13 (36) 5 (14) 003 35 11ndash11Grade 1 4 (11) 3 (8)Grade 2 8 (22) 2 (6)Grade 4 1 (3) 0 (0)

Sepsis 8 (22) 1 (3) 003 01 001ndash084Among infants born before the 32nd week of pregnancy delayed clamping of the umbilical cord (DCC delayed cord clamping 30ndash45 s) reduced the rate ofintraventricular brain hemorrhage (IHV) and neonatal sepsis significantly when compared to immediate severance of the cord (ICC immediate cord clamping5ndash10 s) [94]

explained the significant neuronal improvements observedRecent animal experiments have shown that the applicationof stem cells leads to a significantly improved outcome follow-ing hypoxic-ischemic damage [109ndash111]This neuroprotectiveeffect has recently also been demonstrated in preterm sheepfetuses [112] (Figure 5) The stem cells applied to damagedtissue appear to release numerous factors in the damaged areawhich induce the formation and migration of neuronal stemcells encourage the expansion of dendrites and axons andsuppress postischemic inflammation [111 113] (Figure 6)

Via transmitters mesenchymal stem cells modulatenumerous signaling cascades during apoptosis neurogenesisangiogenesis and synaptogenesis Increased expressions offibroblast growth factor-2 epidermal growth factor glial cellline-derived neurotrophic factor and sonic hedgehog havebeen observed [114] These factors play a central role in theproliferation of progenitor cells as well as in neurogenesisand cell differentiation [115ndash120] (Figure 6) Mesenchymalstem cells stimulate the proliferation of progenitor cells in thedentate gyrus These progenitor cells move into the damagedarea and differentiate under the influence of mesenchymalstem cells into astrocytes oligodendrocytes and neurons[110 121] Additionally stem cells induce the formation ofneuropilin-1 and 2 neuregulin-1 and EphrinB2 messengerswhich play an important role in the regulation of axonalgrowth synapse formation and the integration of the neu-ronal network [114 122] Mesenchymal stem cells supportthe proliferation and differentiation of oligodendrocyte-progenitor cells and thus the myelinisation of the newlyformed axons [110 123 124] Additionally mesenchymalstem cells appear to counteract glial scar formation whichhinders the migration of axons and dendrites [125 126](Figure 6)

Postischemic inflammation is most commonly causedby microglia macrophages of the central nervous systemwhich originate in bone marrow and migrate to the brainduring development where they then differentiate intomicroglia When brain damage occurs these local microgliaare activated and monocytes from peripheral blood alsomigrate to the trauma site [127 128] These so-called M1microglia release proinflammatory cytokines oxygen-basedfree radicals and neurotoxins and further damage the alteredtissue There is an alternative pathway for the activation ofmicroglia (M2) which has neuroprotective effects and leadsto the release of IL-10 insulin growth factor-1 transforming

growth factor-120573 and other immunomodulating factors [128ndash130] The application of mesenchymal stem cells reduces thenumber of classically activated microglia (M1) and thus alsoinhibits the release of proinflammatory cytokines [112 114124] In contrast theM2 cascade is activated with synthesis ofgrowth factors supporting the regeneration of damaged tissue[131 132] (Figure 6)

To what extent effects caused by mesenchymal stem cellscan also be instigated by exosomes remains to be seenExosomes are small membrane vesicles (70ndash120 nm) whichcontain lipids proteins and RNA and which are secreted byvarious types of cells Exosomes obtained frommesenchymalstem cells have been shown to reduce the extent ofmyocardialdamage following ischemia in experiments with adult mice[133]

8 Estradiol and Progesterone

The steroid hormones estradiol and progesterone play acritical role in the growth differentiation and functionof the reproductive system However the peripheral andcentral nervous system is also affected by these hormones asshown by the ubiquitous distribution of the relevant receptors[134ndash137] Estradiol induces axonal and dendritic growthand promotes the development of synapses as well as theintegration of the cerebral cortex [138]

In the third trimester of pregnancy the maternal serumconcentration of estradiol and progesterone increases sig-nificantly and can reach up to 100 times its original level[139 140] Preterm infants are removed abruptly from thisenvironment In animal experiments estradiol has beenshown to protect the immature fetal brain from hypoxic-ischemic lesions [141ndash143] (Figure 7) Progesterone has alsobeen shown to have neuroprotective effects [144] It thereforemakes sense to treat preterm infants with estradiol and pro-gesterone after birth [145] Unfortunately there is currently alack of sufficient clinical data to support such treatment [146]

The neuroprotective effects of estradiol can be impartedreceptor-dependent (genomic and nongenomic) or receptor-independent [147ndash149] The estrogen-receptor independenteffects are the result of the direct antioxidative propertiesof estradiol and of the interaction with potential bindingsites on the neuronal membrane receptors [147]These mem-brane receptors can modulate the neurotransmission andexcitability of the neuronal membrane [150 151] The classic

BioMed Research International 7

Subcortical white matter

lowastlowast

nsns

FA

030

020

010

000

Sham

SALMSC

HI

(a) (b)

(d)(c)

100502510

5

0

1005025105

0

100

0 30 60 90 120

0 30 60 90 120

50

03010 03015 03020 03025 03030 03035 03040

03010 03015 03020 03025 03030 03035 03040

0

minus50

minus100

100

50

0

minus50

minus100

Fron

tal a

EEG

Poste

rior a

EEG

(120583V

)

Fron

tal E

EG(120583

V)

(120583V

)

Poste

rior E

EG(120583

V)

lowast

nsns

SALMSC

Sham HI

Total seizure burden

Seiz

ures

(n)

500

400

300

200

100

0

Dagger

Figure 5 Hypoxic-ischemic brain damage was induced in fetal sheep on the 105th day of gestation (term is at 150 days) by occluding theumbilical cord for 25 minutes One hour after the injury had been inflicted the animals in study group were given iv 35 times 106 mesenchymalstem cells (MSCs) whereas those in the control group received saline (SAL) In sham-operated animals (Sham) occlusion was not carried out(a) Diffusion Tensor Images (DTI) measured using magnetic resonance tomography (MRI) presented as fractional anisotropy (FA) Regionsof interest SCWM (subcortical white matter) and hippocampus (b) Mesenchymal stem cells reduce brain damage in the SCWM measuredas FA Means plusmn 95 CI (lowast119875 lt 005) are depicted Dots show each measurement per animal (c) Representative image of an aEEG trace froman animal of the control group with hypoxic-ischemic brain damage The arrows mark seizures (d) The administration of MSC significantlyreduces the number of seizures (119899) (lowast119875 lt 005 Dagger119875 lt 001) [112]

receptor-mediated effects on neuronal gene transcriptioncause the growth of axons and dendrites the creation ofsynapses the expression of neurotropic factors and increasedacetylcholine synthesis In the central nervous system theestrogen receptor subtypes 120572 und 120573 have been shown to bedifferently distributed and regulated [134 135] Both receptorshave the same affinity for estradiol [152] but differing levels ofaffinity for ldquoestrogen-response-elementsrdquo and have therefore

demonstrated partially different gene activation patterns[153] Two effects of the estradiol receptor-120572 are responsiblefor the antiapoptotic propertiesThe activation of the receptorleads to a rapid induction of the insulin-like growth factor 1(IGF-1) receptor pathway and the associated signal cascade[154] IGF-1 has been shown to have neuroprotective capacity[155] In addition 17120573-estradiol inhibits the caspase-pathwaywhich plays a key role in apoptosis [156]

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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Oxidative Medicine and Cellular Longevity

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 6: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

6 BioMed Research International

Table 2 Neuroprotection by delayed clamping of the umbilical cord

ICC (119873 = 36)119873 () DCC (119873 = 36)119873 () 119875 Odds ratio 95 CIIVH

Total 13 (36) 5 (14) 003 35 11ndash11Grade 1 4 (11) 3 (8)Grade 2 8 (22) 2 (6)Grade 4 1 (3) 0 (0)

Sepsis 8 (22) 1 (3) 003 01 001ndash084Among infants born before the 32nd week of pregnancy delayed clamping of the umbilical cord (DCC delayed cord clamping 30ndash45 s) reduced the rate ofintraventricular brain hemorrhage (IHV) and neonatal sepsis significantly when compared to immediate severance of the cord (ICC immediate cord clamping5ndash10 s) [94]

explained the significant neuronal improvements observedRecent animal experiments have shown that the applicationof stem cells leads to a significantly improved outcome follow-ing hypoxic-ischemic damage [109ndash111]This neuroprotectiveeffect has recently also been demonstrated in preterm sheepfetuses [112] (Figure 5) The stem cells applied to damagedtissue appear to release numerous factors in the damaged areawhich induce the formation and migration of neuronal stemcells encourage the expansion of dendrites and axons andsuppress postischemic inflammation [111 113] (Figure 6)

Via transmitters mesenchymal stem cells modulatenumerous signaling cascades during apoptosis neurogenesisangiogenesis and synaptogenesis Increased expressions offibroblast growth factor-2 epidermal growth factor glial cellline-derived neurotrophic factor and sonic hedgehog havebeen observed [114] These factors play a central role in theproliferation of progenitor cells as well as in neurogenesisand cell differentiation [115ndash120] (Figure 6) Mesenchymalstem cells stimulate the proliferation of progenitor cells in thedentate gyrus These progenitor cells move into the damagedarea and differentiate under the influence of mesenchymalstem cells into astrocytes oligodendrocytes and neurons[110 121] Additionally stem cells induce the formation ofneuropilin-1 and 2 neuregulin-1 and EphrinB2 messengerswhich play an important role in the regulation of axonalgrowth synapse formation and the integration of the neu-ronal network [114 122] Mesenchymal stem cells supportthe proliferation and differentiation of oligodendrocyte-progenitor cells and thus the myelinisation of the newlyformed axons [110 123 124] Additionally mesenchymalstem cells appear to counteract glial scar formation whichhinders the migration of axons and dendrites [125 126](Figure 6)

Postischemic inflammation is most commonly causedby microglia macrophages of the central nervous systemwhich originate in bone marrow and migrate to the brainduring development where they then differentiate intomicroglia When brain damage occurs these local microgliaare activated and monocytes from peripheral blood alsomigrate to the trauma site [127 128] These so-called M1microglia release proinflammatory cytokines oxygen-basedfree radicals and neurotoxins and further damage the alteredtissue There is an alternative pathway for the activation ofmicroglia (M2) which has neuroprotective effects and leadsto the release of IL-10 insulin growth factor-1 transforming

growth factor-120573 and other immunomodulating factors [128ndash130] The application of mesenchymal stem cells reduces thenumber of classically activated microglia (M1) and thus alsoinhibits the release of proinflammatory cytokines [112 114124] In contrast theM2 cascade is activated with synthesis ofgrowth factors supporting the regeneration of damaged tissue[131 132] (Figure 6)

To what extent effects caused by mesenchymal stem cellscan also be instigated by exosomes remains to be seenExosomes are small membrane vesicles (70ndash120 nm) whichcontain lipids proteins and RNA and which are secreted byvarious types of cells Exosomes obtained frommesenchymalstem cells have been shown to reduce the extent ofmyocardialdamage following ischemia in experiments with adult mice[133]

8 Estradiol and Progesterone

The steroid hormones estradiol and progesterone play acritical role in the growth differentiation and functionof the reproductive system However the peripheral andcentral nervous system is also affected by these hormones asshown by the ubiquitous distribution of the relevant receptors[134ndash137] Estradiol induces axonal and dendritic growthand promotes the development of synapses as well as theintegration of the cerebral cortex [138]

In the third trimester of pregnancy the maternal serumconcentration of estradiol and progesterone increases sig-nificantly and can reach up to 100 times its original level[139 140] Preterm infants are removed abruptly from thisenvironment In animal experiments estradiol has beenshown to protect the immature fetal brain from hypoxic-ischemic lesions [141ndash143] (Figure 7) Progesterone has alsobeen shown to have neuroprotective effects [144] It thereforemakes sense to treat preterm infants with estradiol and pro-gesterone after birth [145] Unfortunately there is currently alack of sufficient clinical data to support such treatment [146]

The neuroprotective effects of estradiol can be impartedreceptor-dependent (genomic and nongenomic) or receptor-independent [147ndash149] The estrogen-receptor independenteffects are the result of the direct antioxidative propertiesof estradiol and of the interaction with potential bindingsites on the neuronal membrane receptors [147]These mem-brane receptors can modulate the neurotransmission andexcitability of the neuronal membrane [150 151] The classic

BioMed Research International 7

Subcortical white matter

lowastlowast

nsns

FA

030

020

010

000

Sham

SALMSC

HI

(a) (b)

(d)(c)

100502510

5

0

1005025105

0

100

0 30 60 90 120

0 30 60 90 120

50

03010 03015 03020 03025 03030 03035 03040

03010 03015 03020 03025 03030 03035 03040

0

minus50

minus100

100

50

0

minus50

minus100

Fron

tal a

EEG

Poste

rior a

EEG

(120583V

)

Fron

tal E

EG(120583

V)

(120583V

)

Poste

rior E

EG(120583

V)

lowast

nsns

SALMSC

Sham HI

Total seizure burden

Seiz

ures

(n)

500

400

300

200

100

0

Dagger

Figure 5 Hypoxic-ischemic brain damage was induced in fetal sheep on the 105th day of gestation (term is at 150 days) by occluding theumbilical cord for 25 minutes One hour after the injury had been inflicted the animals in study group were given iv 35 times 106 mesenchymalstem cells (MSCs) whereas those in the control group received saline (SAL) In sham-operated animals (Sham) occlusion was not carried out(a) Diffusion Tensor Images (DTI) measured using magnetic resonance tomography (MRI) presented as fractional anisotropy (FA) Regionsof interest SCWM (subcortical white matter) and hippocampus (b) Mesenchymal stem cells reduce brain damage in the SCWM measuredas FA Means plusmn 95 CI (lowast119875 lt 005) are depicted Dots show each measurement per animal (c) Representative image of an aEEG trace froman animal of the control group with hypoxic-ischemic brain damage The arrows mark seizures (d) The administration of MSC significantlyreduces the number of seizures (119899) (lowast119875 lt 005 Dagger119875 lt 001) [112]

receptor-mediated effects on neuronal gene transcriptioncause the growth of axons and dendrites the creation ofsynapses the expression of neurotropic factors and increasedacetylcholine synthesis In the central nervous system theestrogen receptor subtypes 120572 und 120573 have been shown to bedifferently distributed and regulated [134 135] Both receptorshave the same affinity for estradiol [152] but differing levels ofaffinity for ldquoestrogen-response-elementsrdquo and have therefore

demonstrated partially different gene activation patterns[153] Two effects of the estradiol receptor-120572 are responsiblefor the antiapoptotic propertiesThe activation of the receptorleads to a rapid induction of the insulin-like growth factor 1(IGF-1) receptor pathway and the associated signal cascade[154] IGF-1 has been shown to have neuroprotective capacity[155] In addition 17120573-estradiol inhibits the caspase-pathwaywhich plays a key role in apoptosis [156]

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 7: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

BioMed Research International 7

Subcortical white matter

lowastlowast

nsns

FA

030

020

010

000

Sham

SALMSC

HI

(a) (b)

(d)(c)

100502510

5

0

1005025105

0

100

0 30 60 90 120

0 30 60 90 120

50

03010 03015 03020 03025 03030 03035 03040

03010 03015 03020 03025 03030 03035 03040

0

minus50

minus100

100

50

0

minus50

minus100

Fron

tal a

EEG

Poste

rior a

EEG

(120583V

)

Fron

tal E

EG(120583

V)

(120583V

)

Poste

rior E

EG(120583

V)

lowast

nsns

SALMSC

Sham HI

Total seizure burden

Seiz

ures

(n)

500

400

300

200

100

0

Dagger

Figure 5 Hypoxic-ischemic brain damage was induced in fetal sheep on the 105th day of gestation (term is at 150 days) by occluding theumbilical cord for 25 minutes One hour after the injury had been inflicted the animals in study group were given iv 35 times 106 mesenchymalstem cells (MSCs) whereas those in the control group received saline (SAL) In sham-operated animals (Sham) occlusion was not carried out(a) Diffusion Tensor Images (DTI) measured using magnetic resonance tomography (MRI) presented as fractional anisotropy (FA) Regionsof interest SCWM (subcortical white matter) and hippocampus (b) Mesenchymal stem cells reduce brain damage in the SCWM measuredas FA Means plusmn 95 CI (lowast119875 lt 005) are depicted Dots show each measurement per animal (c) Representative image of an aEEG trace froman animal of the control group with hypoxic-ischemic brain damage The arrows mark seizures (d) The administration of MSC significantlyreduces the number of seizures (119899) (lowast119875 lt 005 Dagger119875 lt 001) [112]

receptor-mediated effects on neuronal gene transcriptioncause the growth of axons and dendrites the creation ofsynapses the expression of neurotropic factors and increasedacetylcholine synthesis In the central nervous system theestrogen receptor subtypes 120572 und 120573 have been shown to bedifferently distributed and regulated [134 135] Both receptorshave the same affinity for estradiol [152] but differing levels ofaffinity for ldquoestrogen-response-elementsrdquo and have therefore

demonstrated partially different gene activation patterns[153] Two effects of the estradiol receptor-120572 are responsiblefor the antiapoptotic propertiesThe activation of the receptorleads to a rapid induction of the insulin-like growth factor 1(IGF-1) receptor pathway and the associated signal cascade[154] IGF-1 has been shown to have neuroprotective capacity[155] In addition 17120573-estradiol inhibits the caspase-pathwaywhich plays a key role in apoptosis [156]

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Disease Markers

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Page 8: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

8 BioMed Research International

NPC

Ischemic brain

Microglia

AstrocyteNeuron

Oligodendrocyte

Modulation of inflammation

NeurogenesisGliogenesisRemyelinationAxonal plasticity

Neuroregeneration

MSC

Figure 6 Neuroregeneration using mesenchymal stem cells (MSCs) following neonatal hypoxia-ischemia After transplantation into anischemically damaged area of the brain mesenchymal stem cells respond to the environment by producing growth and differentiation factorsThese factors stimulate proliferation and differentiation of neural stem cells (NPCs) and stimulate repair processes Upon transplantation ofMSCs microglia are activated and modulate the inflammatory response of the brain contributing to neurorepair [113]

lowast5

4

3

2

1

Scor

e

A1

A2

A3

A4

A5

Sum

H-C

A1

2

H-C

A3

H-C

A4

DG

Cortex Hippocampus

EstradiolNaCl

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

lowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowastlowast

Figure 7 Neuronal cell damage in the cerebral cortex (A1ndashA5) andhippocampus (CA 12 CA3DG) in neonatal rats following hypoxia-ischemiaThe animals in the study group were treated with estradiolboth before and after injury whereas animals of the control groupreceived NaCl Neuronal cell damage was significantly reduced inthe cerebral cortex as well as in the hippocampus after applicationof estradiol Neuronal cell damage was evaluated using a scoringsystem (1 = 0ndash4 2 = 5ndash49 3 = 50ndash94 4 = 95ndash995 = 100 damaged neurons) Means plusmn SD (lowast119875 lt 005 lowastlowastlowast119875 lt 0001)[143]

Theneuroprotective effects of progesterone are alsomedi-ated by various mechanisms Progesterone reduces postis-chemic cellular edema by maintaining the integrity of theblood-brain barrier Increased expressions of claudin5 andoccludin1 have been observed in connection with this pro-cess both of which are proteins that play an important role in

the creation of tight junctions In contrast it has been shownthat the expression of MMP-3 and MMP-9 is reduced Thelatter is involved in extracellular tissue degradation [157 158]Additionally progesterone inhibits postischemic apoptosisand induces the release of the growth factor BNDF as hasbeen demonstrated by investigations using the TUNEL assayand caspase 3 [159] Progesterone suppresses postischemicinflammation by reducing the expression of IL-1120573 TNF-120572IL 6 COX-2 and ICAM-1 [146 149ndash151] It also reducesthe expression of TGF-1205732 VCAM-1 CD68 and Iba1 [160ndash162] factors which play a role in postischemic inflamma-tion The inducible form of NO-synthase is inhibited byprogesterone [163] while the levels of superoxide dismutasecatalase and glutathione peroxidase in tissue are increased[164] The administration of progesterone also leads to theincreased release of GAP43 and synaptophysin both ofwhich are markers for synaptogenesis [165] However onestudy including experiments with rats showed an increase inhypoxic-ischemic brain damage following the administrationof progesterone on the 7th and 14th day of life but not on the21st day [166]

Many more neuroprotective strategies have been investi-gated in animal experiments However a detailed discussionof all of these strategies is outside the scope of this reviewWewould like to invite interested readers to refer to the relevantliterature

Condensation

Clinical and experimental strategies to protect the immaturebrain from ischemic andor infectious injury are reviewed

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

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Page 9: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

BioMed Research International 9

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] Neonatal data from the German federal states (BQS Bunde-sauswertung 2008 Datensatzversion 161 2008 110 Datenbank-stand 15032009 658200 Datensatze)

[2] J J Volpe Neurology of the Newborn WB Saunders 1995[3] G Hambleton and J S Wigglesworth ldquoOrigin of intraventric-

ular haemorrhage in the preterm infantrdquo Archives of Disease inChildhood vol 51 no 9 pp 651ndash659 1976

[4] D M Moody W R Brown V R Challa and S M BlockldquoAlkaline phosphatase histochemical staining in the study ofgerminal matrix hemorrhage and brain vascular morphologyin a very-low-birth-weight neonaterdquo Pediatric Research vol 35no 4 pp 424ndash430 1994

[5] Y Nakamura T Okudera S Fukuda and T HashimotoldquoGerminal matrix hemorrhage of venous origin in pretermneonatesrdquoHuman Pathology vol 21 no 10 pp 1059ndash1062 1990

[6] K C K Kuban and F H Gilles ldquoHuman telencephalic angio-genesisrdquo Annals of Neurology vol 17 no 6 pp 539ndash548 1985

[7] K E Pape and Wigglesworth Haemorrhage Ischemia and thePerinatal Brain J B Lippincott Philadelphia Pa USA 1979

[8] M Funato H Tamai K Noma et al ldquoClinical events in associa-tion with timing of intraventricular hemorrhage in preterminfantsrdquo The Journal of Pediatrics vol 121 no 4 pp 614ndash6191992

[9] R N Goldberg D Chung S L Goldman and E BancalarildquoThe association of rapid volume expansion and intraventricu-lar hemorrhage in the preterm infantrdquoThe Journal of Pediatricsvol 96 no 6 pp 1060ndash1063 1980

[10] A Jensen V Klingmuller W Kunzel and S Sefkow ldquoThe riskof brain haemorrhage in preterms- and in mature newborns-infantsrdquo Geburtshilfe und Frauenheilkunde vol 52 no 1 pp 6ndash20 1992

[11] D W A Milligan ldquoFailure of autoregulation and intraventricu-lar haemorrhage in preterm infantsrdquoThe Lancet vol 1 no 8174pp 896ndash898 1980

[12] R Berger S Bender S Sefkow V Klingmuller W Kunzel andA Jensen ldquoPeriintraventricular haemorrhage a cranial ultra-sound study on 5286 neonatesrdquo European Journal of ObstetricsGynecology and Reproductive Biology vol 75 no 2 pp 191ndash2031997

[13] M Amato J C Fauchere and U Hermann Jr ldquoCoagu-lation abnormalities in low birth weight infants with peri-intraventricular hemorrhagerdquoNeuropediatrics vol 19 no 3 pp154ndash157 1988

[14] B A Lupton A Hill M F Whitfield C J Carter L DWadsworth and E H Roland ldquoReduced platelet count as a riskfactor for intraventricular hemorrhagerdquo The American Journalof Diseases of Children vol 142 no 11 pp 1222ndash1224 1988

[15] A Shirahata T Nakamura M Shimono M Kaneko andS Tanaka ldquoBlood coagulation findings and the efficacy offactor XIII concentrate in premature infants with intracranialhemorrhagesrdquo Thrombosis Research vol 57 no 5 pp 755ndash7631990

[16] J C Larroche Developmental Pathology of the NeonateExcerpta Medica New York NY USA 1997

[17] M G Norman ldquoPerinatal brain damagerdquo Perspectives in Pedi-atric Pathology vol 4 pp 41ndash92 1978

[18] L S de Vries J S Wigglesworth R Regev and L M SDubowitz ldquoEvolution of periventricular leukomalacia duringthe neonatal period and infancy correlation of imaging andpostmortem findingsrdquo Early Human Development vol 17 no2-3 pp 205ndash219 1988

[19] P L Hope S J Gould S Howard P A Hamilton A ML Costello and E O R Reynolds ldquoPrecision of ultrasounddiagnosis of pathologically verified lesions in the brains of verypreterm infantsrdquo Developmental Medicine amp Child Neurologyvol 30 no 4 pp 457ndash471 1988

[20] N Paneth R RudelliWMonte et al ldquoWhitematter necrosis invery low birth weight infants neuropathologic and ultrasono-graphic findings in infants surviving six days or longerrdquo TheJournal of Pediatrics vol 116 no 6 pp 975ndash984 1990

[21] M Dambska M Laure-Kamionowska and B Schmidt-SidorldquoEarly and late neuropathological changes in perinatal whitematter damagerdquo Journal of Child Neurology vol 4 no 4 pp291ndash298 1989

[22] SMDe laMonte F I Hsu E THedley-Whyte andWKupskyldquoMorphometric analysis of the human infant brain effects ofintraventricular hemorrhage and periventricular leukomala-ciardquo Journal of Child Neurology vol 5 no 2 pp 101ndash110 1990

[23] F H Gilles and S F Murphy ldquoPerinatal telencephalic leucoen-cephalopathyrdquo Journal of Neurology Neurosurgery and Psychia-try vol 32 no 5 pp 404ndash413 1969

[24] F H Gilles A Leviton and E C Dooling The DevelopingHuman Brain Growth and Epidemiologic Neuropathology JohnWright PSG Boston Mass USA 1983

[25] A Quasebarth Periventrikulare Leukomalazie und PerinataleTelenzephale Leukoenzephalopathie Ein und dieselbe KrankheitEine neuropathologische Studie anhand von 10 FalldarstellungenGoethe University Frankfurt Frankfurt Germany 2001

[26] J L De Reuck ldquoCerebral angioarchitecture and perinatal brainlesions in premature and full-term infantsrdquo Acta NeurologicaScandinavica vol 70 no 6 pp 391ndash395 1984

[27] L B Rorke ldquoAnatomical features of the developing brainimplicated in pathogenesis of hypoxic-ischemic injuryrdquo BrainPathology vol 2 no 3 pp 211ndash221 1992

[28] S Takashima D L Armstrong and L E Becker ldquoSubcorticalleukomalacia Relationship to development of the cerebralsulcus and its vascular supplyrdquo Archives of Neurology vol 35no 7 pp 470ndash472 1978

[29] W Szymonowicz A M Walker V Y H Yu M L StewartJ Cannata and L Cussen ldquoRegional cerebral blood flowafter hemorrhagic hypotension in the preterm near-term andnewborn lambrdquo Pediatric Research vol 28 no 4 pp 361ndash3661990

[30] O Dammann and A Leviton ldquoMaternal intrauterine infectioncytokines and brain damage in the pretermnewbornrdquo PediatricResearch vol 42 no 1 pp 1ndash8 1997

[31] S K Sinha J M Davies D G Sims and M L ChiswickldquoRelation between periventricular haemorrhage and ischaemicbrain lesions diagnosed by ultrasound in very pre-term infantsrdquoThe Lancet vol 2 no 8465 pp 1154ndash1156 1985

[32] U Verma N Tejani S Klein et al ldquoObstetric antecedentsof intraventricular hemorrhage periventricular leukomalaciain the low-birth-weight neonaterdquo The American Journal ofObstetrics and Gynecology vol 176 no 2 pp 275ndash281 1997

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 10: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

10 BioMed Research International

[33] R Romero Z A Savasan T Chaiworapongsa et al ldquoHemato-logic profile of the fetus with systemic inflammatory responsesyndromerdquo Journal of Perinatal Medicine vol 40 no 1 pp 19ndash32 2011

[34] Y Garnier A Coumans R Berger A Jensen and T HM Hasaart ldquoEndotoxemia severely affects circulation duringnormoxia and asphyxia in immature fetal sheeprdquo Journal of theSociety for Gynecologic Investigation vol 8 no 3 pp 134ndash1422001

[35] Y Garnier A B C Coumans A Jensen T H M Hasaartand R Berger ldquoInfection-related perinatal brain injury thepathogenic role of impaired fetal cardiovascular controlrdquo Jour-nal of the Society for Gynecologic Investigation vol 10 no 8 pp450ndash459 2003

[36] H N Liu B I Giasson W E Mushynski and G AlmazanldquoAMPA receptor-mediated toxicity in oligodendrocyte progen-itors involves free radical generation and activation of JNKcalpain and caspase 3rdquo Journal of Neurochemistry vol 82 no2 pp 398ndash409 2002

[37] A B C Coumans J Middelanis Y Garnier et al ldquoIntracis-ternal application of endotoxin enhances the susceptibility tosubsequent hypoxic-ischemic brain damage in neonatal ratsrdquoPediatric Research vol 53 no 5 pp 770ndash775 2003

[38] B Feldhaus I D Dietzel R Heumann and R Berger ldquoEffectsof interferon-120574 and tumor necrosis factor-120572 on survival anddifferentiation of oligodendrocyte progenitorsrdquo Journal of theSociety for Gynecologic Investigation vol 11 no 2 pp 89ndash962004

[39] Y W Wu and J M Colford ldquoChorioamnionitis as a risk factorfor cerebral palsy a meta-analysisrdquo Journal of the AmericanMedical Association vol 284 no 11 pp 1417ndash1424 2000

[40] J G Shatrov S C Birch L T Lam J A Quinlivan S McIntyreandG LMendz ldquoChorioamnionitis and cerebral palsy ameta-analysisrdquoObstetrics ampGynecology vol 116 no 2 part 1 pp 387ndash392 2010

[41] V T Guinto B De Guia M R Festin and T Dowswell ldquoDif-ferent antibiotic regimens for treating asymptomatic bacteriuriain pregnancyrdquo Cochrane Database of Aystematic Reviews vol 9Article ID CD007855 2010

[42] P Brocklehurst A Gordon E Heatley and S J Milan ldquoAntibi-otics for treating bacterial vaginosis in pregnancyrdquo CochraneDatabase of Systematic Reviews Article ID CD000262 2013

[43] D Subtil G Brabant E Tilloy et al ldquoEarly clindamycin forbacterial vaginosis in low-risk pregnancy the PREMEVA1 ran-domized multicenter double-blind placebo-controlled trialrdquoAmerican Journal of Obstetrics amp Gynecology vol 210 no 1supplement p S3 2014

[44] E B Da Fonseca R E Bittar M H B Carvalho and MZugaib ldquoProphylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontaneous pretermbirth in women at increased risk a randomized placebo-controlled double-blind studyrdquo American Journal of Obstetricsand Gynecology vol 188 no 2 pp 419ndash424 2003

[45] P J Meis M Klebanoff EThom et al ldquoPrevention of recurrentpreterm delivery by 17 120572-hydroxyprogesterone caproaterdquo TheNew England Journal of Medicine vol 348 no 24 pp 2379ndash2385 2003

[46] P J Meis M Klebanoff EThom et al ldquoCorrection Preventionof recurrent preterm delivery by 17 120572-hydroxyprogesteronecaproaterdquo The New England Journal of Medicine vol 349 no13 p 1299 2003

[47] E B Fonseca E CelikM ParraM Singh KHNicolaides andFetal Medicine Foundation Second Trimester Screening GroupldquoProgesterone and the risk of preterm birth among womenwitha short cervixrdquo The New England Journal of Medicine vol 357no 5 pp 462ndash469 2007

[48] S S Hassan R Romero D Vidyadhari et al ldquoVaginal pro-gesterone reduces the rate of preterm birth in women with asonographic short cervix a multicenter randomized double-blind placebo-controlled trialrdquo Ultrasound in Obstetrics andGynecology vol 38 no 1 pp 18ndash31 2011

[49] P Rai S Rajaram N Goel R Ayalur Gopalakrishnan RAgarwal and S Mehta ldquoOral micronized progesterone for pre-vention of preterm birthrdquo International Journal of Gynecologyand Obstetrics vol 104 no 1 pp 40ndash43 2009

[50] J Owen G Hankins J D Iams et al ldquoMulticenter randomizedtrial of cerclage for preterm birth prevention in high-riskwomenwith shortenedmidtrimester cervical lengthrdquoAmericanJournal of Obstetrics amp Gynecology vol 201 no 4 pp 375e1ndash375e8 2009

[51] V Berghella T J Rafael J M Szychowski O A Rust and JOwen ldquoCerclage for short cervix on ultrasonography in womenwith singleton gestations and previous preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 117 no 3 pp 663ndash6712011

[52] V Berghella and A D MacKeen ldquoCervical length screeningwith ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth a meta-analysisrdquo Obstetrics and Gynecology vol 118 no 1 pp 148ndash1552011

[53] M Elovitz and Z Wang ldquoMedroxyprogesterone acetate butnot progesterone protects against inflammation-induced par-turition and intrauterine fetal demiserdquo American Journal ofObstetrics and Gynecology vol 190 no 3 pp 693ndash701 2004

[54] M A Elovitz and C Mrinalini ldquoCan medroxyprogesteroneacetate alter Toll-like receptor expression in a mouse model ofintrauterine inflammationrdquoTheAmerican Journal of Obstetricsand Gynecology vol 193 no 3 part 2 pp 1149ndash1155 2005

[55] L W Doyle C A Crowther P Middleton S Marret and DRouse ldquoMagnesium sulphate for women at risk of pretermbirth for neuroprotection of the fetusrdquo Cochrane Database ofSystematic Reviews no 1 Article ID CD004661 2009

[56] American College of Obstetricians andGynecologists Commit-tee on Obstetric Practice Society for Maternal-Fetal MedicineldquoCommittee Opinion No 573 magnesium sulfate use in obstet-ricsrdquo Obstetrics and Gynecology vol 122 no 3 pp 727ndash7282013

[57] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[58] R Berger and Y Garnier ldquoPathophysiology of perinatal braindamagerdquo Brain Research Reviews vol 30 no 2 pp 107ndash1341999

[59] L Nowak P Bregestovski P Ascher A Herbet and A Prochi-antz ldquoMagnesium gates glutamate-activated channels in mousecentral neuronesrdquoNature vol 307 no 5950 pp 462ndash465 1984

[60] M Hallak J W Hotra and W J Kupsky ldquoMagnesium sulfateprotection of fetal rat brain from severe maternal hypoxiardquoObstetrics and Gynecology vol 96 no 1 pp 124ndash128 2000

[61] A G Euser and M J Cipolla ldquoMagnesium sulfate for thetreatment of eclampsia a brief reviewrdquo Stroke vol 40 no 4 pp1169ndash1175 2009

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 11: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

BioMed Research International 11

[62] M Farago C Szabo E Dora I Horvath and A G B KovachldquoContractile and endothelium-dependent dilatory responses ofcerebral arteries at various extracellular magnesium concentra-tionsrdquo Journal of Cerebral Blood Flow and Metabolism vol 11no 1 pp 161ndash164 1991

[63] Y Garnier J Middelanis A Jensen and R Berger ldquoNeu-roprotective effects of magnesium on metabolic disturbancesin fetal hippocampal slices after oxygen-glucose deprivationmediation by nitric oxide systemrdquo Journal of the Society forGynecologic Investigation vol 9 no 2 pp 86ndash92 2002

[64] K B Nelson and J K Grether ldquoCan magnesium sulfate reducethe risk of cerebral palsy in very low birthweight infantsrdquoPediatrics vol 95 no 2 pp 263ndash269 1995

[65] J C Hauth R L Goldenberg K G Nelson M B DuBard MA Peralta and F L Gaudier ldquoReduction of cerebral palsy withmaternal MgSO

4treatment in newborns weighing 500ndash1000 grdquo

American Journal of Obstetrics amp Gynecology vol 172 p 4191995

[66] D E Schendel C J Berg M Yeargin-Allsopp C A Boyleand P Decoufle ldquoPrenatal magnesium sulfate exposure and therisk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 yearsrdquo Journal of the AmericanMedical Association vol 276 no 22 pp 1805ndash1810 1996

[67] T E Wiswell L J Graziani J L Caddell N Vecchione CStanley andA R Spitzer ldquoMaternally administeredmagnesiumsulphate protects against early brain injury and long-termadverse neurodevelopmental outcomes in preterm infants aprospective studyrdquo Pediatric Research vol 39 p 253 1996

[68] Y Matsuda S Kouno Y Hiroyama et al ldquoIntrauterine infec-tion magnesium sulfate exposure and cerebral palsy in infantsborn between 26 and 30 weeks of gestationrdquo European Journalof Obstetrics Gynecology and Reproductive Biology vol 91 no 2pp 159ndash164 2000

[69] N Paneth J Jetton J Pinto-Martin andM Susser ldquoMagnesiumsulfate in labor and risk of neonatal brain lesions and cerebralpalsy in low birth weight infants The Neonatal Brain Hemor-rhage StudyAnalysis GrouprdquoPediatrics vol 99 no 5 p E1 1997

[70] T M OrsquoShea K L Klinepeter and R G Dillard ldquoPrenatalevents and the risk of cerebral palsy in very low birth weightinfantsrdquo American Journal of Epidemiology vol 147 no 4 pp362ndash369 1998

[71] D Wilson-Costello E Borawski H Friedman R Redline AA Fanaroff andM Hack ldquoPerinatal correlates of cerebral palsyand other neurologic impairment among very low birth weightchildrenrdquo Pediatrics vol 102 no 2 pp 315ndash322 1998

[72] C A Boyle M Yeargin-Allsopp D E Schendel P Holmgreenand G P Oakley ldquoTocolytic magnesium sulfate exposure andrisk of cerebral palsy among children with birth weights lessthan 1750 gramsrdquo American Journal of Epidemiology vol 152no 2 pp 120ndash124 2000

[73] J K Grether J Hoogstrate E Walsh-Greene and K BNelson ldquoMagnesium sulfate for tocolysis and risk of spasticcerebral palsy in premature children born to women withoutpreeclampsiardquo American Journal of Obstetrics and Gynecologyvol 183 no 3 pp 717ndash725 2000

[74] MMCostantine H YHow K Coppage R AMaxwell and BM Sibai ldquoDoes peripartum infection increase the incidence ofcerebral palsy in extremely low birthweight infantsrdquo AmericanJournal of Obstetrics and Gynecology vol 196 no 5 pp e8ndashe82007

[75] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in preterm

labor and adverse health outcomes in infantsrdquo The AmericanJournal of Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[76] C A Crowther J E Hiller L W Doyle R R Haslamand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMg SO4) Collaborative Group ldquoEffect of magnesiumsulfate given for neuroprotection before preterm birth a ran-domized controlled trialrdquo The Journal of the American MedicalAssociation vol 290 no 20 pp 2669ndash2676 2003

[77] Magpie Trial Follow-Up Study Collaborative Group ldquoTheMag-pie Trial a randomised trial comparing magnesium sulphatewith placebo for pre-eclampsia Outcome for children at 18monthsrdquo BJOG An International Journal of Obstetrics amp Gynae-cology vol 114 no 3 pp 289ndash299 2007

[78] S Marret L Marpeau C Follet-Bouhamed et al ldquoEffect ofmagnesium sulphate on mortality and neurologic morbidityof the very-preterm newborn with two-year neurological out-come results of the prospective PREMAG trialrdquo GynecologieObstetrique Fertilite vol 36 no 3 pp 278ndash288 2008

[79] D J Rouse D G Hirtz and E Thom ldquoEunice kennedy shriverNICHDmaternal-fetal medicine units network A randomizedcontrolled trial of magnesium sulfate for the prevention ofcerebral palsyrdquo The New England Journal of Medicine vol 359no 9 pp 895ndash905 2008

[80] L W Doyle P J Anderson R Haslam K J Lee C Crowtherand Australasian Collaborative Trial of Magnesium Sulphate(ACTOMgSO4) Study Group ldquoSchool-age outcomes of verypreterm infants after antenatal treatment with magnesiumsulfate vs placebordquo The Journal of the American Medical Asso-ciation vol 312 no 11 pp 1105ndash1113 2014

[81] A Conde-Agudelo and R Romero ldquoAntenatal magnesium sul-fate for the prevention of cerebral palsy in preterm infants lessthan 34 weeksrsquo gestation a systematic review andmetaanalysisrdquoAmerican Journal of Obstetrics amp Gynecology vol 200 no 6 pp595ndash609 2009

[82] A G Cahill and A B Caughey ldquoMagnesium for neuroprophy-laxis fact or fictionrdquo The American Journal of Obstetrics andGynecology vol 200 no 6 pp 590ndash594 2009

[83] R Mittendorf J Dambrosia P G Pryde et al ldquoAssociationbetween the use of antenatal magnesium sulfate in pretermlabor and adverse health outcomes in infantsrdquoAmerican Journalof Obstetrics and Gynecology vol 186 no 6 pp 1111ndash1118 2002

[84] L L Ow A Kennedy E A McCarthy and S P WalkerldquoFeasibility of implementingmagnesium sulphate for neuropro-tection in a tertiary obstetric unitrdquoAustralian and New ZealandJournal of Obstetrics and Gynaecology vol 52 no 4 pp 356ndash360 2012

[85] ldquoX4PB Pradiktion und Pravention der Fruhgeb urtrdquo DerFrauenarzt vol 54 pp 1060ndash1071 2013

[86] A C Yao and J Lind ldquoBlood flow in the umbilical vessels duringthe third stage of laborrdquo Biology of the Neonate vol 25 no 3-4pp 186ndash193 1974

[87] G J Hofmeyr K D Bolton D C Bowen and J J GovanldquoPeriventricularintraventricular haemorrhage and umbilicalcord clampings Findings and hypothesisrdquo South African Medi-cal Journal vol 73 no 2 pp 104ndash106 1988

[88] O Baenziger F Stolkin M Keel et al ldquoThe influence of thetiming of cord clamping on postnatal cerebral oxygenation inpreterm neonates a randomized controlled trialrdquo Pediatricsvol 119 no 3 pp 455ndash459 2007

[89] J Bonnar G P McNicol and A S Douglas ldquoThe bloodcoagulation and fibrinolytic systems the newborn and the

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 12: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

12 BioMed Research International

mother at birthrdquo Journal of Obstetrics and Gynaecology of theBritish Commonwealth vol 78 no 4 pp 355ndash360 1971

[90] D-H Park C V Borlongan A E Willing et al ldquoHumanumbilical cord blood cell grafts for brain ischemiardquo Cell Trans-plantation vol 18 no 9 pp 985ndash998 2009

[91] H Rabe A Wacker G Hulskamp et al ldquoA randomisedcontrolled trial of delayed cord clamping in very low birthweight preterm infantsrdquo European Journal of Pediatrics vol 159no 10 pp 775ndash777 2000

[92] M McDonnell and D J Henderson-Smart ldquoDelayed umbilicalcord clamping in preterm infants a feasibility studyrdquo Journal ofPaediatrics and Child Health vol 33 no 4 pp 308ndash310 1997

[93] S Kinmond T C Aitchison B M Holland J G Jones T LTurner and C A J Wardrop ldquoUmbilical cord clamping andpreterm infants a randomised trialrdquo British Medical Journalvol 306 no 6871 pp 172ndash175 1993

[94] J S Mercer B R Vohr M M McGrath J F Padbury MWallach and W Oh ldquoDelayed cord clamping in very preterminfants reduces the incidence of intraventricular hemorrhageand late-onset sepsis a randomized controlled trialrdquo Pediatricsvol 117 no 4 pp 1235ndash1242 2006

[95] American College of Obstetricians and Gynecologists ldquoCom-mittee Opinion No543 timing of umbilical cord clamping afterbirthrdquo Obstetrics amp Gynecology vol 120 no 6 pp 1522ndash15262012

[96] H Rabe A Jewison R Fernandez Alvarez et al ldquoMilkingcompared with delayed cord clamping to increase placentaltransfusion in pretermneonates a randomized controlled trialrdquoObstetrics and Gynecology vol 117 no 2 pp 205ndash211 2011

[97] L Bennet V Roelfsema P Pathipati J S Quaedackers andA JGunn ldquoRelationship between evolving epileptiform activity anddelayed loss of mitochondrial activity after asphyxia measuredby near-infrared spectroscopy in preterm fetal sheeprdquo Journalof Physiology vol 572 no 1 pp 141ndash154 2006

[98] A J Gunn T R Gunn H H de Haan C E Williams andP D Gluckman ldquoDramatic neuronal rescue with prolongedselective head cooling after ischemia in fetal lambsrdquoThe Journalof Clinical Investigation vol 99 no 2 pp 248ndash256 1997

[99] E C Jensen L Bennet C JHunter G C Power andA J GunnldquoPost-hypoxic hypoperfusion is associated with suppression ofcerebral metabolism and increased tissue oxygenation in near-term fetal sheeprdquo Journal of Physiology vol 572 no 1 pp 131ndash139 2006

[100] A Lorek Y Takei E B Cady et al ldquoDelayed (lsquosecondaryrsquo)cerebral energy failure after acute hypoxia-ischemia in thenewborn piglet continuous 48-hour studies by phosphorusmagnetic resonance spectroscopyrdquo Pediatric Research vol 36no 6 pp 699ndash706 1994

[101] S C Roth J Baudin E Cady et al ldquoRelation of derangedneonatal cerebral oxidative metabolism with neurodevelop-mental outcome and head circumference at 4 yearsrdquo Develop-mental Medicine and Child Neurology vol 39 no 11 pp 718ndash725 1997

[102] F Colbourne and D Corbett ldquoDelayed postischemic hypother-mia a six month survival study using behavioral and histolog-ical assessments of neuroprotectionrdquo Journal of Neurosciencevol 15 no 11 pp 7250ndash7260 1995

[103] R Geddes R C Vannucci and S J Vannucci ldquoDelayed cerebralatrophy following moderate hypoxia-ischemia in the immatureratrdquo Developmental Neuroscience vol 23 no 3 pp 180ndash1852001

[104] B S Stone J Zhang D W Mack S Mori L J Martin andF J Northington ldquoDelayed neural network degeneration afterneonatal hypoxia-ischemiardquo Annals of Neurology vol 64 no 5pp 535ndash546 2008

[105] R D Barrett L Bennet J Davidson et al ldquoDestruction andreconstruction hypoxia and the developing brainrdquoBirthDefectsResearch Part C Embryo Today Reviews vol 81 no 3 pp 163ndash176 2007

[106] A J Friedenstein R K Chailakhyan N V Latsinik A FPanasyuk and I V Keiliss-Borok ldquoStromal cells responsible fortransferring the microenvironment of the hemopoietic tissuesCloning in vitro and retransplantation in vivordquoTransplantationvol 17 no 4 pp 331ndash340 1974

[107] M Najar G Raicevic H I Boufker et al ldquoAdipose-tissue-derived and Whartonrsquos jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factorrdquo Tissue Engineering Part A vol 16 no 11 pp3537ndash3546 2010

[108] S Yust-Katz Y Fisher-Shoval Y Barhum et al ldquoPlacentalmesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells from hypoxia and oxida-tive stressrdquo Cytotherapy vol 14 no 1 pp 45ndash55 2012

[109] C Meier J Middelanis B Wasielewski et al ldquoSpastic paresisafter perinatal brain damage in rats is reduced by human cordblood mononuclear cellsrdquo Pediatric Research vol 59 no 2 pp244ndash249 2006

[110] C T J van Velthoven A Kavelaars F van Bel and CJ Heijnen ldquoMesenchymal stem cell treatment after neona-tal hypoxic-ischemic brain injury improves behavioral out-come and induces neuronal and oligodendrocyte regenerationrdquoBrain Behavior and Immunity vol 24 no 3 pp 387ndash393 2010

[111] J A Lee B I Kim C H Jo et al ldquoMesenchymal stem-celltransplantation for hypoxic-ischemic brain injury in neonatalrat modelrdquo Pediatric Research vol 67 no 1 pp 42ndash46 2010

[112] R K Jellema T G A M Wolfs V Lima Passos et alldquoMesenchymal stemcells induceT-cell tolerance andprotect thepreterm brain after global hypoxia-ischemiardquo PLoS ONE vol 8no 8 Article ID e73031 2013

[113] C T J van Velthoven A Kavelaars and C J Heijnen ldquoMes-enchymal stem cells as a treatment for neonatal ischemic braindamagerdquo Pediatric Research vol 71 no 4 part 2 pp 474ndash4812012

[114] C T J vn Velthoven A Kavelaars F van Bel and C JHeijnen ldquoMesenchymal stem cell transplantation changes thegene expression profile of the neonatal ischemic brainrdquo BrainBehavior and Immunity vol 25 no 7 pp 1342ndash1348 2011

[115] A Gritti P Frolichsthal-Schoeller R Galli et al ldquoEpidermaland fibroblast growth factors behave as mitogenic regulatorsfor a single multipotent stem cell-like population from thesubventricular region of the adult mouse forebrainrdquoThe Journalof Neuroscience vol 19 no 9 pp 3287ndash3297 1999

[116] B A Reynolds and S Weiss ldquoGeneration of neurons andastrocytes from isolated cells of the adult mammalian centralnervous systemrdquo Science vol 255 no 5052 pp 1707ndash1710 1992

[117] T Kobayashi H Ahlenius P Thored R Kobayashi Z KokaiaandO Lindvall ldquoIntracerebral infusion of glial cell line-derivedneurotrophic factor promotes striatal neurogenesis after strokein adult ratsrdquo Stroke vol 37 no 9 pp 2361ndash2367 2006

[118] L H Shen Y Li and M Chopp ldquoAstrocytic endogenousglial cell derived neurotrophic factor production is enhancedby bone marrow stromal cell transplantation in the ischemic

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 13: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

BioMed Research International 13

boundary zone after stroke in adult ratsrdquo GLIA vol 58 no 9pp 1074ndash1081 2010

[119] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 no 1 pp 21ndash27 2003

[120] K Lai B K Kaspar F H Gage and D V Schaffer ldquoSonichedgehog regulates adult neural progenitor proliferation in vitroand in vivordquo Nature Neuroscience vol 6 pp 21ndash27 2003

[121] R J Felling M J Snyder M J Romanko et al ldquoNeuralstemprogenitor cells participate in the regenerative responseto perinatal hypoxiaischemiardquoThe Journal of Neuroscience vol26 no 16 pp 4359ndash4369 2006

[122] S T Carmichael ldquoCellular andmolecularmechanisms of neuralrepair after stroke making wavesrdquo Annals of Neurology vol 59no 5 pp 735ndash742 2006

[123] F J Rivera M Kandasamy S Couillard-Despres et al ldquoOligo-dendrogenesis of adult neural progenitors differential effects ofciliary neurotrophic factor and mesenchymal stem cell derivedfactorsrdquo Journal of Neurochemistry vol 107 no 3 pp 832ndash8432008

[124] C T J van Velthoven A Kavelaars F van Bel and C JHeijnen ldquoRepeated mesenchymal stem cell treatment afterneonatal hypoxia-ischemia has distinct effects on formation andmaturation of new neurons and oligodendrocytes leading torestoration of damage corticospinal motor tract activity andsensorimotor functionrdquoThe Journal of Neuroscience vol 30 no28 pp 9603ndash9611 2010

[125] Y Li J Chen C L Zhang et al ldquoGliosis and brain remodelingafter treatment of stroke in rats with marrow stromal cellsrdquoGLIA vol 49 no 3 pp 407ndash417 2005

[126] L H Shen Y Li Q Gao S Savant-Bhonsale and M ChoppldquoDown-regulation of neurocan expression in reactive astrocytespromotes axonal regeneration and facilitates the neurorestora-tive effects of bone marrow stromal cells in the ischemic ratbrainrdquo GLIA vol 56 no 16 pp 1747ndash1754 2008

[127] C T Ekdahl Z Kokaia and O Lindvall ldquoBrain inflammationand adult neurogenesis the dual role of microgliardquo Neuro-science vol 158 no 3 pp 1021ndash1029 2009

[128] M Czeh P Gressens and A M Kaindl ldquoThe yin and yangof microgliardquo Developmental Neuroscience vol 33 no 3-4 pp199ndash209 2011

[129] U-K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007

[130] M Schwartz O Butovsky W Bruck and U-K HanischldquoMicroglial phenotype is the commitment reversiblerdquo Trendsin Neurosciences vol 29 no 2 pp 68ndash74 2006

[131] J AarumK Sandberg S L BHaeberlein andMAA PerssonldquoMigration and differentiation of neural precursor cells can bedirected by microgliardquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 26 pp15983ndash15988 2003

[132] P Thored U Heldmann W Gomes-Leal et al ldquoLong-termaccumulation of microglia with proneurogenic phenotype con-comitant with persistent neurogenesis in adult subventricularzone after strokerdquo GLIA vol 57 no 8 pp 835ndash849 2009

[133] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[134] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in

the rat central nervous systemrdquo The Journal of ComparativeNeurology vol 388 no 4 pp 507ndash525 1997

[135] N Laflamme R E Nappi G Drolet C Labrie and S RivestldquoExpression and neuropeptidergic characterization of estrogenreceptors (ER120572 and ER120573) throughout the rat brain anatomicalevidence of distinct roles of each subtyperdquo Journal of Neurobi-ology vol 36 no 3 pp 357ndash378 1998

[136] A E Clipperton-Allen A W Lee A Reyes et al ldquoOxytocinvasopressin and estrogen receptor gene expression in relation tosocial recognition in female micerdquo Physiology amp Behavior vol105 no 4 pp 915ndash924 2012

[137] D G Zuloaga S L Yahn Y Pang et al ldquoDistribution andestrogen regulation of membrane progesterone receptor-120573 inthe female rat brainrdquo Endocrinology vol 153 no 9 pp 4432ndash4443 2012

[138] S Haraguchi K Sasahara H Shikimi S-I Honda N Haradaand K Tsutsui ldquoEstradiol promotes purkinje dendritic growthspinogenesis and synaptogenesis during neonatal life by induc-ing the expression of BDNFrdquo Cerebellum vol 11 no 2 pp 416ndash417 2012

[139] D Tulchinsky C J Hobel E Yeager and J R MarshallldquoPlasma estradiol estriol and progesterone in human preg-nancy II Clinical applications in Rh-isoimmunization diseaserdquoThe American Journal of Obstetrics and Gynecology vol 113 no6 pp 766ndash770 1972

[140] C E Wood ldquoEstrogenhypothalamus-pituitary-adrenal axisinteractions in the fetus the interplay between placenta andfetal brainrdquo Journal of the Society for Gynecologic Investigationvol 12 no 2 pp 67ndash76 2005

[141] J Nunez Z Yang Y Jiang T Grandys I Mark and SW Levison ldquo17120573-Estradiol protects the neonatal brain fromhypoxia-ischemiardquo Experimental Neurology vol 208 no 2 pp269ndash276 2007

[142] B Gerstner J Lee T M DeSilva F E Jensen J J Volpe and PA Rosenberg ldquo17120573-estradiol protects against hypoxicischemicwhite matter damage in the neonatal rat brainrdquo Journal ofNeuroscience Research vol 87 no 9 pp 2078ndash2086 2009

[143] M M Muller J Middelanis C Meier D Surbek and RBerger ldquo17120573-estradiol protects 7-day old rats from acute braininjury and reduces the number of apoptotic cellsrdquo ReproductiveSciences vol 20 no 3 pp 253ndash261 2013

[144] E R Deutsch T R Espinoza F Atif E Woodall J Kaylor andD W Wright ldquoProgesteronersquos role in neuroprotection a reviewof the evidencerdquo Brain Research vol 1530 pp 82ndash105 2013

[145] A Trotter L Maier and F Pohlandt ldquoManagement of theextremely preterm infant is the replacement of estradiol andprogesterone beneficialrdquoPaediatricDrugs vol 3 no 9 pp 629ndash637 2001

[146] R Hunt P G Davis and T Inder ldquoReplacement of estrogensand progestins to prevent morbidity and mortality in preterminfantsrdquo The Cochrane Database of Systematic Reviews no 4Article ID CD003848 2004

[147] C Behl and F Holsboer ldquoThe female sex hormone oestrogen asa neuroprotectantrdquo Trends in Pharmacological Sciences vol 20no 11 pp 441ndash444 1999

[148] C Behl ldquoOestrogen as a neuroprotective hormonerdquo NatureReviews Neuroscience vol 3 no 6 pp 433ndash442 2002

[149] S J Lee and B S McEwen ldquoNeurotrophic and neuroprotectiveactions of estrogens and their therapeutic implicationsrdquoAnnualReview of Pharmacology and Toxicology vol 41 pp 569ndash5912001

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 14: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

14 BioMed Research International

[150] R J Bicknell ldquoSex-steroid actions on neurotransmissionrdquoCurrent Opinion in Neurology vol 11 no 6 pp 667ndash671 1998

[151] Q Gu K S Korach and R L Moss ldquoRapid action of 17120573-estradiol on kainate-induced currents in hippocampal neuronslacking intracellular estrogen receptorsrdquo Endocrinology vol140 no 2 pp 660ndash666 1999

[152] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and alpha and betardquo Endocrinologyvol 138 no 3 pp 863ndash870 1997

[153] S M Hyder C Chiappetta and G M Stancel ldquoInteractionof human estrogen receptors 120572 and 120573 with the same naturallyoccurring estrogen response elementsrdquoBiochemical Pharmacol-ogy vol 57 no 6 pp 597ndash601 1999

[154] S Kahlert S Nuedling M van Eickels H Vetter R Meyerand C Grohe ldquoEstrogen receptor a rapidly activates the IGF-1receptor pathwayrdquoThe Journal of Biological Chemistry vol 275no 24 pp 18447ndash18453 2000

[155] K G Brywe CMallardM Gustavsson et al ldquoIGF-I neuropro-tection in the immature brain after hypoxia-ischemia involve-ment of Akt and GSK3120573rdquo European Journal of Neurosciencevol 21 no 6 pp 1489ndash1502 2005

[156] Y Zhang O Tounekti B Akerman C G Goodyer andA LeBlanc ldquo17-beta-estradiol induces an inhibitor of activecaspasesrdquo The Journal of Neuroscience vol 21 no 20 articleRC176 2001

[157] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoPro-gesterone and allopregnanolone attenuate blood-brain barrierdysfunction following permanent focal ischemia by regulatingthe expression of matrix metalloproteinasesrdquo ExperimentalNeurology vol 226 no 1 pp 183ndash190 2010

[158] C-Y Xu S Li X-Q Li and D-L Li ldquoEffect of progesteroneon MMP-3 expression in neonatal rat brain after hypoxic-ischemiardquo Zhongguo Ying Yong Sheng Li Xue Za Zhi vol 26 no3 pp 370ndash373 2010

[159] T Ishrat I Sayeed F Atif F Hua and D G Stein ldquoProges-terone is neuroprotective against ischemic brain injury throughits effects on the phosphoinositide 3-kinaseprotein kinase Bsignaling pathwayrdquo Neuroscience vol 210 pp 442ndash450 2012

[160] C L Gibson D Constantin M J W Prior P M W Bathand S P Murphy ldquoProgesterone suppresses the inflammatoryresponse and nitric oxide synthase-2 expression followingcerebral ischemiardquo Experimental Neurology vol 193 no 2 pp522ndash530 2005

[161] C Jiang K Cui J Wang and Y He ldquoMicroglia andcyclooxygenase-2 possible therapeutic targets of progesteronefor strokerdquo International Immunopharmacology vol 11 no 11pp 1925ndash1931 2011

[162] J Wang Y Zhao C Liu C Jiang C Zhao and Z ZhuldquoProgesterone inhibits inflammatory response pathways afterpermanent middle cerebral artery occlusion in ratsrdquoMolecularMedicine Reports vol 4 no 2 pp 319ndash324 2011

[163] T Coughlan C Gibson and S Murphy ldquoModulatory effects ofprogesterone on inducible nitric oxide synthase expression invivo and in vitrordquo Journal of Neurochemistry vol 93 no 4 pp932ndash942 2005

[164] R Aggarwal B Medhi A Pathak V Dhawan and AChakrabarti ldquoNeuroprotective effect of progesterone on acutephase changes induced by partial global cerebral ischaemia inmicerdquo Journal of Pharmacy and Pharmacology vol 60 no 6pp 731ndash737 2013

[165] Y Zhao J Wang C Liu C Jiang C Zhao and Z ZhuldquoProgesterone influences postischemic synaptogenesis in theCA1 region of the hippocampus in ratsrdquo Synapse vol 65 no9 pp 880ndash891 2011

[166] M Tsuji A Taguchi M Ohshima Y Kasahara and T IkedaldquoProgesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature ratsrdquo ExperimentalNeurology vol 233 no 1 pp 214ndash220 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 15: ReviewArticle Neuroprotection in Preterm Infants€¦ · ReviewArticle Neuroprotection in Preterm Infants R.BergerandS.Söder MarienhausKlinikumSt.Elisabeth,DepartmentofObstetricsandGynecology,56564Neuwied,Germany

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom