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Selenium and stroke
we areresearch
selenase®
• eliminatesseleniumdeficiency
• stroke impairs selenium status
• highseleniumstatuscorrelates withpositiveoutcome
Sodium selenite for stroke
• Strokepatientsshowsignificantlyreducedseleniumlevels [1]
• Highglutathioneperoxidaseconcentrationcorrelateswithlow neurologicaldeficiencyandapositiveoutcomeafterastroke [1]
• SignificantlyreducedselenoproteinPconcentrationinpatientsafter anacutestroke [2]
• ReducedselenoproteinPstatusisassociatedwithasignificantlyhigherrisk for stroke [2]
Sodium selenite for stroke*
Day1 Bolusdirectlyafteradmission to ICU 2,000 [A] µg Se
Day2–5 Maintenancetherapy 1,000 [A]µgSe/day
*ongoingclinicaltrial
[A]NCT02505295“Seleniumandischemicstrokeoutcome”.
Bynowarandomized,double-blinded,placebocontrolledtrialwiththetitle“Seleniumandischemicstrokeoutcome”(NCT02505295)isunderway,whichinvestigateswhetheradministrationof2,000μgseleniuminform of selenase®immediatelyafterpatientadmissionaswellas1,000μgseleniumperday(selenase®)forfivedaysreducesmortalityandneuro-logicaldamage.
SELENIUM AND STROKE2
Compatibility
Yes No
•5%glucosesolution• Ringer solution•Carbohydratesolutions•Electrolytesolutions withincreasedpotassiumconcentration
•Crystalloidelectrolyte solutions
•Cytostaticagentsolutions [I]
•Aminoacidsolutions thatcontaincysteine [II]
•Solutionsthatcontain glutathione(GSH) [III]
• Vitamin solutions thatcontainvitaminC [IV]
[I] selenase®shouldgenerallybeadministered considerablybefore thecytostaticagent.[II, III] SHgroupsreactwithsodiumselenite;sodiumselenitecannolongerfulfillitstaskasaradicalscavenger. [A]
[IV] Selenium (Se+IV)insodiumseleniteisreducedbyvitaminCtotheelementaryselenium(Se0)andistherebyineffective.[B–D]
[A] TsenCCetal.JBiolChem.1958Nov;233(5):1230-2.Catalyticoxidationofglutathioneandothersulfhydrylcompoundsbyselenite.
[B] RobinsonMFetal.NZMedJ.1985Aug14;98(784):627-9.Effectofamegadoseofascorbicacid,amealandorangejuiceontheabsorptionofseleniumassodiumselenite.
[C] IpC.JNatlCancerInst.1986Jul;77(1):299-303.InteractionofvitaminCandseleniumsupplementationinthemodificationofmammarycarcinogenesisinrats.
[D] Summaryofproductcharacteristicsselenase®,biosynArzneimittelGmbH,versionNovember2017.
SELENIUM AND STROKE 3
Summary
Ischemia/reperfusion
Selenium inthebrain
Seleniumisessentialforthebrain
Glutathioneperoxidase1influencestheinfarctvolume
Glutathioneperoxidase4isessentialinbraindevelopment
Glutathioneperoxidase4playsaroleinneuropathologicaldiseases
ThelackoftheseleniumtransportproteinselenoproteinPcausesneurologicaldysfunctionsthatcanbeattenuatedbyadministering sodium selenite
Sodium selenite for stroke
Studieshaveshown:
Sodiumseleniteactsneuroprotectivelyevenhoursafterinductionofthedamage
Seleniumdeficitresultsinamassiveincreaseinsusceptibilityforexcitotoxicityandincreasedneuronalcellloss
Theneuroprotectiveeffectofsodiumseleniteisbasedon:
• thereductionofoxidativestressinneurons
• thepreservationofthemitochondrialrespiratorychain
• theinhibitionofNFκBandAP1activation
• theinhibitionofischemia-inducedDNAoxidation
• thenormalizationofischemia-activatedautophagy
Selenium status and selenoprotein activityintheeventof a stroke
Strokepatientsshowsignificantlyreducedseleniumvalues
Highglutathioneperoxidaseconcentrationcorrelateswithalowneurologicaldeficitandafavorableoutcomeforstroke
SignificantlyreducedselenoproteinPconcentration inpatientswithanacutestroke
AreducedselenoproteinPlevelisassociatedwithasignificantlyhigherriskofstroke
SELENIUM AND STROKE4
Tableofcontents
7 Seleniuminthebrain
7 Seleniumisessentialforthebrain
8 Glutathioneperoxidase1influencestheinfarctvolume
10 Glutathioneperoxidase4:essentialforbraindevelopment
10 Glutathioneperoxidase-4playsaroleinneuropathologicaldiseases
12 SelenoproteinPknock-outcausessevereneurologicaldysfunction
14 Sodium selenite for stroke
14 Sodiumseleniteactsneuroprotectivelyevenhoursafterinductionofthedamage
18 Seleniumdeficitmassivelyincreasessusceptibilitytoexcitotoxicity andincreasedneuronalcellloss
20 Principleofactionofneuronalprotectionbysodiumselenite
21 Sodiumselenitepreservesthemitochondrialrespiratorychainafterhypoxia
21 SodiumseleniteinhibitsNFκB-andAP-1activation
22 Effectofsodiumseleniteisdependentonthebiosynthesisofselenoproteins
22 Sodiumselenitereducesischemia-inducedDNAoxidation
24 Sodiumselenitenormalizesischemia-activatedautophagy
25 Impactofaseleniumdeficitonthebrainaffectedbystroke
26 Seleniumstatusandselenoproteinactivityintheeventofastroke
26 Strokepatientsshowsignificantlydecreasedseleniumvalues
28 Correlationbetweenglutathioneperoxidaseconcentration,neurologicaldeficit,andoutcome
30 SignificantlyreducedselenoproteinPconcentrationinpatientswithanacutestroke
32 Attachment
32 Bibliography
33 Selenium in guidelines
34 Productsforinjectiontherapy
35 InformationonbiosynArzneimittelGmbH
36 Imprint
5
Seleniumplaysanimportantroleinthebrain
Ataglance
Seleniumplaysanimportantroleinthebrain
Studieshaveshown:Glutathioneperoxidase1influences theinfarctvolume
Glutathioneperoxidase4isessentialforbraindevelopment andplaysaroleinneuropathologicaldiseases
ThelackoftheseleniumtransportproteinselenoproteinPcausesneurologicaldysfunctionsthatcanbeattenuatedbyadministeringsodium selenite
Seleniuminthebrain
Seleniumisessentialforthebrain
Thetotalamountofseleniuminthebrainiscomparativelylow.Inthebrain,aconcentrationof110±21ngselenium/gwetweightwasdeter-minedinGermanadults.Incontrast,thereis771±169ngselenium/ginthekidneyand291±78ngselenium/gintheliver.Thebrainthuscontainsonly2.3%oftheentireseleniuminahumanbody.[3]Preferentiallytheavailableseleniumistransportedtothebrainattheexpanseofotherorgans,suchastheliver,ifmammalsareonalong-termlowseleniumdiet.[4]Approximately20%oftheentireseleniumamountinthebrainisincorporatedintoglutathioneperoxidase.[4]Withasufficientseleniumsupply,theglutathioneperoxidaseactivityintheliveris13timesgreaterthaninthebrain(animalexperiment).Afteraselenium-deficitdietofabout6months,theactivityoftheglutathioneperoxidasewasreducedby92%intheliver,whileinthebrainitonlydeclinednegligibly.[5]
Seleniumplaysanimportantroleforvariousdiseasesofthecentralnervoussystem(CNS),amongothersstroke,braintumors,braindevel-opment and neurodegenerative diseases.[6]Firstindicationsweredeliv-eredbyreportsaboutneurologicaldiseasesinpatientswithlowseleniumstatusorrestrictedselenoproteinbiosynthesis.Overalongtimeperiod,parenterallynourishedpatientswithinadequateseleniumcontentdevel-opedamongothersprogressiveencepalopathy.[7] Two rare mutations of thehumanSEPSECSgenethatcodestheselenocysteinesynthaseleadtoprogressivecerebellarandcerebralatrophy.[8]
SELENIUM IN THE BRAIN 7
Glutathioneperoxidase1influences theinfarctvolume
Asalreadylongknown,micewithknock-outofglutathioneperoxidase1(GxP1)showa3-foldincreaseofinfarctvolumecomparedwithwild-typemice(p<0.01)(Fig. 1).[9]Thisisalsoreflectedintheincreasednumberofnecroticandapoptoticcells.Anearlieractivationofcaspase3inGPx1knock-outmicemoreoverindicatesincreasedsusceptibilitytoapoptosisinGPx1knock-outmice.
Furthermore,aninvestigationwithtransgenicmice,whichoverexpressedglutathioneperoxidase,revealedasignificantreductionintheinfarctvolumeinconsequenceofI/Rdamagecomparedwithnon-transgenicmice. [10]Anoverexpressionofglutathioneperoxidasesignificantlyreducedbothnecroticaswellasapoptoticcelldeathinendangeredbrainregions(p<0.05).Intheseanimals,theactivationofastrocytomaandmicrogliaintheischemicbrainwasreduced.Incontrasttowildtype-mice,glutathioneperoxidaseoverexpressingmiceshowedasignificantlybetterpreservedtissuestructureandareducedinfiltrationofacuteinflammatorycells(p<0.05). [10]
SELENIUM IN THE BRAIN8
3-foldincreasedinfarctvolumeforglutathioneperoxidase1(GPx1)knock-outmice
Infa
rct v
olum
e [m
m3 ]
GPx1 wildtype mice GPx1 knock-out mice
p < 0.01
0
50
100
150
Createdaccordingto:CrackPJetal.JNeurochem.2001Sep;78(6):1389-99.Increasedinfarctsizeandexacerbatedapoptosisintheglutathioneperoxidase-1 (Gpx-1)knockoutmousebraininresponsetoischemia/reperfusioninjury.
Fig. 1
SELENIUM IN THE BRAIN 9
Glutathioneperoxidase4: essentialforbraindevelopment
Glutathioneperoxidase4(GPx4)isessentialforsurvival.HomozygousGPx4knock-outmicedieinuterointhemiddletrimesterduetomalforma-tions. [11]GPx4isexpressedinneurons,particularlyinthehippocampus. [12] Meanwhile,itwasdemonstratedthattheneuronalGPx4expressionplaysanessentialneuroprotectiveroleinMorbusParkinson.[13] In addi-tion,GPx4modulatestheinterneuronaldevelopmentinthenervesofthenigostriaticpathwayaswellastheexpressionofparvalbumin.[14]Further-more,GPx4preventsseizuresandneurodegeneration.[14]
Glutathioneperoxidase-4playsaroleinneuropathologicaldiseases
GPx4isamultifunctionalantioxidativeproteinwithanti-apoptoticchar-acteristics. [12]Thisisparticularlyrelevantbecauseneurons,incontrasttoglialcells,essentiallydependontheirGPxactivitytodetoxifyfreeoxygenradicals(ROS)andlipidperoxides.[15]IncreasedROSlevelsoccurinneu-ropathologicaldisorderssuchastrauma,seizureandischemia.Further-more,ithasbeenshownthatthecytosolicvariantsofGPx4areup-reg-ulatedafterbraininjuries. [12]Howeverthisdoesnotoccurinneurons,butratherinreactiveastrocytes,aglialcelltypethatdoesnotexpressGPX4undernormalconditions.Afterbraininjuries,astrocyteschangetheircytoskeletonandmigrateinthedirectionofthelesion,wheretheyareinvolvedintherepairofoligodendrocytesandmyelination,aswellasinthere-establishmentoftheblood-brainbarrierinordertopreventneuroinflammation. [12]ThereforeexpressionofGPx4intheastrocytesisthereforearesponsetostressthatprovidesneuro-protectiontopreventadditionaldamage.AsodiumseleniteadministrationinthephysiologicalrangewithzebrafishsignificantlyincreasedtheGPx4expressioninthebraincomparedtoselenium-deficientzebrafish(p=0.048)(Fig. 2).[16] ApartfromGPx4,otherselenoproteinssuchasSEPN1andGPx3alsohaveneuroprotectivefunctionsbyneutralizingreactiveoxygenspecies.[17] Overall,theseresultssuggestthatasodiumseleniteadministrationincreasestheantioxidativecapacityofthebrain.
SELENIUM IN THE BRAIN10
SodiumseleniteadministrationinthephysiologicalrangesignificantlyincreasesGPx4expressioninthebrain
p < 0.05
Rel
ativ
e ex
pres
sion
of
Glu
tath
ionp
erox
idas
e 4
in th
e br
ain
[log 2]
-0.05Sodium selenite
groupControl group
0
0.05
0.10
0.15
Createdaccordingto:BennerMJetal.PhysiolGenomics.2013Aug1;45(15):653-66.Sex-specifictranscriptionalresponsesofthezebrafish(Daniorerio)brainselenoproteometoacutesodiumselenitesupplementation.
Fig. 2
SELENIUM IN THE BRAIN 11
SelenoproteinPknock-outcausessevereneurologicaldysfunction
Almostallknownselenoproteinscanbefoundinthebrain,wherebythetransportproteinforselenium,selenoproteinP(SEPP1),makessele-niumavailableintheformofselenocysteinefortheexpressionofsele-noproteins.AnanimalstudyshowedthatseleniumfromSEPP1couldbedetectedinthebrainevenaftertwohours.ThisindicatesthatthebrainhasanuptakemechanismforSEPP1.[18]The“knock-out”ofSEPP1leadstodecreasedseleniumconcentrationandselenoproteinactivitiesinthebrain.[19,20]SEPP1knock-outmicedevelopedbrainfunctiondisordersandshowedlimitedmotorcoordinationwithanadequateseleniumdietprovidedbysodiumselenite. [21]However,theneurologicaldisorderswithanadequateseleniumdietusingselenomethionineweresomassivethatalmosthalfoftheSEPP1knock-outmicehadtobeeuthanized.Asodiumseleniteadministrationabovethedailynormalseleniumrequirementcouldpreventbrainfunctiondisorders(Fig. 3). [21]
Moreover,significantlygreaterneurologicaldysfunctionsoccurredwithmaleanimalsinSEPP1knock-outmice(p<0.001). [22] Treatment withsodiumseleniteattenuatedthemotoricdeficitsofmaleanimalstoagreaterdegree(p<0.001).
SELENIUM IN THE BRAIN12
SEPP1knock-outmice:improvementofbrainfunctiondisorderswithsupraphysiologicaladministrationofsodium selenite
Stri
de le
ngth
[cm
]
00 0.1 0.25
Sodium selenite administration [mg/kg]
2
4
6
p < 0.05p < 0.05SEPP1 wildtype mice
SEPP1 knock-out mice
Modifiedaccordingto:HillKEetal.JNutr.2004Jan;134(1):157-61.NeurologicaldysfunctionoccursinmicewithtargeteddeletionoftheselenoproteinPgene.
Fig. 3
SELENIUM IN THE BRAIN 13
Sodiumseleniteactsneuroprotectively evenhoursafterinductionofthedamage
Savaskan et al. investigated the role of sele-nium for stroke in vitro and in animal exper-iments.Glutamatewasemployedforthesimulation of a stroke.[23] It is the predominant stimulatingneurotransmitterinthebrain.Underpathologicalconditionssuchasstroke,epilepsyandtraumaticbraindamage,glutamatecanbetoxicforneurons.Experimentshaveshownthatsimultaneous administration of sodium selenite inaconcentration-dependentmannerpreventedglutamate-inducedcelldeath(p<0.01)(Fig. 4), wherebythegreatesteffect(98%protection)wasdeterminedforaconcentrationof100nM
sodiumselenite,aconcentrationthatliesinthehumanphysiologicalrange.Glutamate-inducedcelldeathcouldnotonlybepreventedwiththesimultaneous administration of sodium sele-nite,butreducedalsowithasodiumseleniteadministrationtwohoursaftertheglutamate-induceddamage(p<0.001)(Fig. 5). These resultswereconfirmedinanadditionalstudybyMehta et al.[24]Bothasignificantneuroprotectiveeffectofsodiumselenitewithglutamatetoxicityaswellaswithhypoxia(p<0.001orp<0.05)was demonstrated.
Ataglance
Animalandcellstudiesshow:
Sodiumseleniteactsneuroprotectivelyevenhoursafterinductionof the damage
Seleniumdeficitresultsinmassivelyincreasedsusceptibility toexcitotoxicityandgreaterneuronalcellloss
Accordingtostudies,theneuroprotectiveeffectofsodiumseleniteisbasedon:
•thereductionofoxidativestressinneurons
•thepreservationofthemitochondrialrespiratorychain
•theinhibitionofNFκB-andAP1activation
•theinhibitionoftheischemia-inducedDNAoxidation
•thenormalizationofischemia-activatedautophagy
Sodium selenite for stroke
SODIUM SELENITE FOR STROKE14
Concentration-dependentneuronalprotection of sodium selenite
00
20
40
60
80
100
120
0.01 0.1 0.5 1 5 10
Sodium selenite concentration [µM]
Neu
ropr
otec
tion
[%]
p < 0.01
Modifiedaccordingto:SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4. Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 4
Asodiumseleniteadministrationinthephysiologicalrangeafter2hoursreducedneuronaldeath
p < 0.01
p < 0.01
0
20
40
60
80
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120
Control
Cel
l via
bilit
y [%
]
Sodiumselenite
Sodiumselenite +glutamate
Glutamate
Modifiedaccordingto:SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4. Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 5
SODIUM SELENITE FOR STROKE 15
Thecomparisonofneurologicaldamageinischemiawithandwithoutsodiumseleniteadministrationrevealedsignificantlylessneurologicaldeficitswithaninterventionofsodiumselenite(p<0.05orp<0.01)(ani-malexperiment)(Fig. 6).[25]Alsothedeathofbraincellswithischemiawassignificantlyreducedby38%withsodiumseleniteadministration(p<0.05)(Fig. 7).[25]
A7-daysodiumselenitetreatmentbeforeischemiaresultedinasignif-icantreductionofbraindamageinvivo(p<0.01)(Fig. 8).[24]Theinfarctvolumewastherebyreducedfrom36.4±24.5%to11.6±5.0%comparedtothecontrolgroup24hoursafterre-establishmentofthecirculation.Thisinvivoresultclearlyshowstheneuroprotectiveeffectofsodiumselenitefor strokes.
Significantimprovementoftheneurologicaloutcome in sodium selenite group
0
20
30
50
10
40
60
Beh
avio
ral s
core
p < 0.001
Flexion Spontaneous movement
p < 0.05 p < 0.001 p < 0.01
Control
Ischemia
Ischemia + sodium selenite
Sodium selenite
Modifiedaccordingto:YousufSetal.BrainRes.2007May25;1147:218-25. Seleniumplaysamodulatoryroleagainstcerebralischemia-inducedneuronaldamageinrathippocampus.
Fig. 6
SODIUM SELENITE FOR STROKE16
Significantlylowerinductionofapoptosisinthesodiumselenite group
0
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10
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40
60C
aspa
se-3
act
ivat
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[% c
hang
e of
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troll]
Control Ischemia Ischemia +sodium selenite
Sodiumselenite
p < 0.001 p < 0.05
+ 160 % - 38 %
Modifiedaccordingto:YousufSetal.BrainRes.2007May25;1147:218-25. Seleniumplaysamodulatoryroleagainstcerebralischemia-inducedneuronaldamageinrathippocampus.
Fig. 7
Sodiumselenitereducesbraindamagecausedbyischemia
p < 0.05
0
20
40
60
80
Control
Infa
rct v
olum
e [%
]
Sodium selenite
Modifiedaccordingto:MehtaSLetal.BMCNeurosci.2012Jul9;13:79.Selenium preservesmitochondrialfunction,stimulatesmitochondrialbiogenesis,andreducesinfarctvolumeafterfocalcerebralischemia.
Fig. 8
SODIUM SELENITE FOR STROKE 17
Seleniumdeficitmassivelyincreases susceptibilitytoexcitotoxicity andincreasedneuronalcellloss
Inordertoconfirmthisinvitroresult,ratswereadministeredaselenium-adequateordeficientdiet.[23]Theresultconfirmedthehierarchyofseleniumdistributionunderselenium-deficitconditions.Aselenium-poordietinratsresultedinadramaticreductionoftheseleniumconcen-trationintheliver(p<0.001),whileinthebrain,theseleniumlevelwassignificantlyreducedbutonlyby10%(p<0.01)(Fig. 9).[23]
Inakainatemodel(kainate=structuralanalogsofglutamate)forexcitotoxicityitwashowevershownthatthis10%reductionoftheseleniumlevelinthebrainsufficedtoproducesignifi-cantlyhigherseizurerates(p < 0.01)(Fig. 10). [23] Moreover,selenium-deficitratsshowedsignifi-cantlymoreapoptoticneuronsandtheneuronalcelllossinthehippocampuswassignificantlyhigherthaninratsfedaselenium-adequatediet(p < 0.01)(Fig. 11).
Preferentialseleniumsupplyofthebrainincaseofseleniumdeficiency
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
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eniu
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m c
once
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Adequateselenium diet
Liver Brain
Deficitselenium diet
Adequateselenium diet
Deficitselenium diet
p < 0.001 p < 0.01
Modifiedaccordingto:SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4.Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 9
SODIUM SELENITE FOR STROKE18
Higherneuronalcelllossinthehippocampus with low selenium diet
0
50
75
125
25
100
Num
ber o
f apo
ptot
ic C
A1
neur
ons
Selenium deficientdiet + control
Selenium deficientdiet + kainate
Adequate seleniumdiet + kainate
p < 0.01
p < 0.001
SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4.Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 11
Seleniumdeficitleadstosignificantlyhigherseizureratesinthebrain
0-30 0 30 60 90 120 150 180
0.5
1.0
1.5
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zure
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ivity
Time after kainate injection [min]
Selenium deficient diet + kainate
Adequate selenium diet + kainate
Control
SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4.Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 10
SODIUM SELENITE FOR STROKE 19
Principleofactionofneuronalprotection bysodiumselenite
Sodiumselenitereducesoxidativestressinneurons
Asurplusofglutamateinduceshighlevelsofreactiveoxygenspecies(ROS)inneuronsandtherebystronglyincreasesoxidativestress.SodiumseleniteadministrationpreventstheproductionofROS(p<0.01)(Fig. 12),whilehavingnoinfluenceontheglutathionelevel.[23] Also in thestudybyMehtaetal,sodiumselenitesignificantlyreducedthepro-ductionofROSinducedbyglutamatetoxicityandhypoxia(p<0.001orp<0.05).[24]Thisleadstotheconclusionthattheunderlyingmechanismsofsodiumselenite-mediatedneuronalprotectionlieinthesignificantattenuation of oxidative stress.
Sodiumselenitereducestheincidenceofoxidativestress in stroke patients
0
20
40
60
80
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120
140
160
Per
oxid
e le
vel [
RO
S]
Control Sodium selenite+ glutamate
Glutamate
p < 0.01
Modifiedaccordingto:SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4. Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 12
SODIUM SELENITE FOR STROKE20
Sodiumselenitepreservesthemitochondrialrespiratorychainafterhypoxia
HypoxiasignificantlyreducestheactivityofthecomplexI–IVoftherespi-ratorychain(p<0.01).[24] Cell studies have shown that pretreatment with sodiumselenitefirstincreasestheactivityoftheindividualcomplexestothebaselinevalue,andsecondlysignificantlyreducestheinhibitingeffectofthehypoxiaontherespiratorychain(Table 1). An administration ofsodiumselenitethusalleviatedthenegativeeffectofhypoxiaonthemitochondrialrespiratorychain,wherebytheactivityofthecomplexeseitherremainedatanormallevelorsignificantlyimprovedcomparedtotheconditionwithoutsodiumselenite.
Sodiumseleniteinhibits NFκB-andAP-1activation
GlutamatetreatmentresultedinincreasednuclearNFκBandAP-1level.Thisincreasecouldbeinhibitedbysodiumselenite.[23]Thegel-shiftassayshowedclearlythattheglutamate-inducedactivationandbondingofNFκBandAP-1ontheir“nuclearresponseelements”wasreducedbysodiumselenite.ThemissingactivationofNFκBandAP-1preventsneu-ronalcelldeathandreducestheactivationofglialcells.Theglialactiva-tionraisesstresssignalsandneuronaldamagetoahigherpower,whichleadstosecondarycelldeath(“secondhit”).[27]
Sodiumselenitereducesthenegativeeffectofhypoxiaontherespiratorychain
Hypoxia Hypoxia+ sodium selenite
p value
Complex I -37% -5% p<0.01
Complex II + III -65% -45%
Complex IV -24% -3% p<0.001
Createdaccordingto:MehtaSLetal.BMCNeurosci.2012Jul9;13:79.Selenium preservesmitochondrialfunction,stimulatesmitochondrialbiogenesis,andreducesinfarctvolumeafterfocalcerebralischemia.
Table 1
SODIUM SELENITE FOR STROKE 21
Effectofsodiumseleniteisdependent onthebiosynthesisofselenoproteins
Incontrasttosodiumselenite,sodiumselenatehasnodirectantioxida-tivecharacteristics,butratherisonlyincorporatedinselenoproteins.Aftersodiumselenitewasreplacedbysodiumselenate,mostoftheneuropro-tectiveprotection(70%)remainedpreserved.[23] This suggests that the neuroprotectiveeffectofsodiumselenitedependsonthebiosynthesisofselenoprotein.Theadditionofcycloheximide,whichinhibitsproteinbio-synthesis,cancelledtheneuroprotectiveeffectofsodiumselenitetherebysupportsthehypothesis(Fig. 13).
Sodiumselenitereducedischemia-inducedDNA oxidation
Mehtaetal.conductedananimalexperimenttoexamineaswellifcere-bralischemiainducesoxidativeDNAdamage.[24]Theevidenceof8-OHdGrevealedasignificantincreaseintheoxidativedamage24hoursafterre-establishmentofcirculation.Incomparisontothis,apretreatmentwithsodiumselenitesignificantlyreducedtheoxidativeDNAdamage(p<0.05)(Fig. 14).Thisshowsthattheantioxidativeeffectofsodiumselenitecon-sistsofavoidingDNAoxidationandthedamagesitcauses.
SODIUM SELENITE FOR STROKE22
Theadditionoftheproteinsynthesisinhibitorcycloheximidecancelstheneuroprotectiveeffectof sodium selenite
0
50
75
125
25
100C
ell v
iabi
lity
[%]
Control Sodium selenite+ glutamate
Sodium selenite+ glutamate
+ cycloheximid
Glutamate
p < 0.01 p < 0.001
Modifiedaccordingto:SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4.Selenium deficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 13
SodiumselenitereducesDNAoxidationinduced byischemia
0
20
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50
10
40
8-O
HdG
pos
itive
cel
ls
Control Sodium selenite
p < 0.05
Modifiedaccordingto:MehtaSLetal.BMCNeurosci.2012Jul9;13:79.Selenium preservesmitochondrialfunction,stimulatesmitochondrialbiogenesis,andreducesinfarctvolumeafterfocalcerebralischemia.
Fig. 14
SODIUM SELENITE FOR STROKE 23
Sodiumselenitenormalizes ischemia-activatedautophagy
Inordertoremovedamagedorganellesandcelldebrisafteracerebralischemia,autophagyisactivated.LC3-IIisamarkerofautophagy.ThemeasurementofLC3-IIafteraninducedischemiarevealedinanimalstudiesasignificantincreaseafterfivehours(p<0.001)andadeclinetotheoriginallevelafter24hours(Fig. 15).[24]Inratsthatreceivedsodiumseleniteforsevendays,theincreaseofLC3-IIafterfivehourswassig-nificantlylower(p<0.001).After24hourstheLC3-IIlevelreductionwashighlysignificantcomparedtothecontrolgroup(p<0.001).Apretreat-mentwithsodiumselenitepreventedbraindamagecausedbyischemia,whichiswhytherewaslessactivationofautophagy.[24]
Sodiumseleniteinhibitstheactivationofautophagyaftercerebralischemia
0
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100
LC3-
II re
lativ
e in
tens
ity
Control 5 h 24 h Control 5 h 24 h
p < 0.01
p < 0.001 p < 0.001
p < 0.05150
Saline
Sodium selenite
Modifiedaccordingto:MehtaSLetal.BMCNeurosci.2012Jul9;13:79.Selenium preservesmitochondrialfunction,stimulatesmitochondrialbiogenesis,andreducesinfarctvolumeafterfocalcerebralischemia.
Fig. 15
SODIUM SELENITE FOR STROKE24
Impactofaseleniumdeficitonthebrainaffectedbystroke
See figure 16.
Effectofaseleniumdeficit(rightside)onthebrainaffectedbystroke,ischemiaandbraintrauma*
Glutamate-induced seizure
Glutamate releasecalcium influx
Tissue damageSeizures
Glutamate releasecalcium influx
With sodium selenite pre-treatment Control group
Oxidative stress Oxidative stress
NFκB
Glialactivation
Neuroncell death
Tissue damageSeizures
NFκB
Glialactivation
Neuroncell death
* Results from animal experiments and in vitro studies
Modifiedaccordingto:SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4. Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
Fig. 16
SODIUM SELENITE FOR STROKE 25
Strokepatientsshowsignificantly decreasedseleniumvalues
AtrialbyZimmermannetal.hascomparedtheantioxidantstatusofpatientswithacutestroke(n=11)withpatientswhohadsufferedastrokeintheprevious12months(n=17). [1] In patients with a stroke anamnesis, theaverageserumseleniumconcentrationof73.4±11.1μg/lwasbelowthereferencevalueof80μg/lseleniuminserum.Valuesbelow80μg/lseleniuminserumareconsideredasseleniumdeficit.Incomparison,theserumseleniumlevelinpatientswithanacutestrokeshowedsignificantlylowerseleniumvalues(61.6±9.5µg/l;p<0.01)(Fig. 17).
Ataglance
Strokepatientsshowsignificantlydecreasedseleniumvalues
Correlationbetweenglutathioneperoxidaseconcentration,neurologicaldeficit,andoutcome
SignificantlyreducedselenoproteinPinpatientswithanacutestroke
AreducedselenoproteinPstatusissignificantlyassociatedwitha higher stroke risk
Selenium status and selenoproteinactivityinthe event of a stroke
SELENIUM STATUS AND SELENOPROTEIN ACTIVITY26
Significantlyreducedserumseleniumconcentration inpatientswithacutestroke
p < 0.01Reference range
Patients withstroke within
last 12 months
Patients withacute stroke,
admissionto ICU
Patients withacute stroke
Day 1
Patients withacute stroke
Day 2
Patients withacute stroke
Day 7
0
10
20
30
40
50
60
70
80
90
100
Ser
um s
elen
ium
con
cent
ratio
n [µ
g/l]
Createdaccordingto:ZimmermannCetal.EurNeurol.2004;51(3):157-61.Antioxidantstatusinacutestrokepatientsandpatientsatstrokerisk.
Fig. 17
SELENIUM STATUS AND SELENOPROTEIN ACTIVITY 27
Correlationbetween glutathioneperoxidaseconcentration,neurologicaldeficit,andoutcome
Measurementoftheselenium-dependent,antioxidantglutathioneperoxi-dasedisplayedasignificantincreaseoftheglutathioneperoxidaselevelinacutestrokepatientsondayone(p<0.05)(Fig. 18). In half of the patientswhohadsufferedastrokeintheprevious12months,thegluta-thionelevelswerebelowthenormalrange.Incontrast,theglutathioneconcentrationinpatientswithanacutestrokewassignificantlyincreased(p<0.01)(Fig. 19).Moreover,therewasanegativecorrelationbetweentheglutathioneperoxidaseconcentrationandtheNIHSS(NationalInsti-tuteofHealthStrokeScale)atadmission(r=-0.84;p<0.001)andaftersevendays(r=-0.63;p<0.05).Highglutathioneperoxidaseconcen-trationscorrelatedwithalowneurologicaldeficit(lowerNIHSSvalueatadmission)andwithafavorableoutcome(lowerNIHSSvalueondayseven).Theseresultsconfirmedfindingsacquiredinanimalexperiments,i.e.thatglutathioneperoxidasecanhaveaprotectiveeffectagainstbraindamageandthatareducedglutathioneperoxidaselevelisassociatedwithincreasedstrokerisk. [1]
SELENIUM STATUS AND SELENOPROTEIN ACTIVITY28
Significantincreaseofglutathioneperoxidaseconcentrationinpatientswithacutestroke
0
100
50
150
200
Patients withstroke within
last 12 months
Patients withacute stroke,
admissionto ICU
Patients withacute stroke
Day 1
Patients withacute stroke
Day 3
Patients withacute stroke
Day 7
Glu
tath
ione
per
oxid
ase
conc
entra
tion
in s
erum
[U/l]
p < 0.05
Createdaccordingto:ZimmermannCetal.EurNeurol.2004;51(3):157-61.Antioxidantstatusinacutestrokepatientsandpatientsatstrokerisk.
Fig. 18
Significantlyincreasedglutathioneconcentration inpatientswithacutestroke
Patients withacute stroke
Day 1
Patients withacute stroke
Day 3
Patients withacute stroke,
admissionto ICU
Patients withacute stroke
Day 7
Patients withstroke within
last 12 months
0
40
20
60
80
100
120
Glu
tath
ione
con
cent
ratio
n in
blo
od [µ
mol
/l]
p < 0.01
Createdaccordingto:ZimmermannCetal.EurNeurol.2004;51(3):157-61.Antioxidantstatusinacutestrokepatientsandpatientsatstrokerisk.
Fig. 19
SELENIUM STATUS AND SELENOPROTEIN ACTIVITY 29
SignificantlyreducedselenoproteinPconcentrationinpatientswithanacutestroke
Inapopulation-basedembeddedcase-controltrialwith1,632participants,Koyamaetal.comparedtheserumseleniumandselenoproteinPcon-centrationsof30strokepatientswith30controls. [2] The serum selenium concentrationwaslower(105.2vs116.5µg/l;p=0.054)instrokepatients.TheresultiscomparabletotheZimmermanntrial.Acomparisonofthetwostudies,however,alsoshowsthatthelocalizationofastudyplaysamajorroleincaseofselenium.InEurope,theseleniumlevelsarelowercomparedtoJapan.[1,2,26]Apartfromtheserumseleniumconcentration,theselenoproteinPconcentrationinstrokepatientswassignificantlylower(54.5vs.63.9µg/l;p=0.006)(Table 2). A multivariate regression analysisshowedthatareducedselenoproteinPlevelisassociatedwithhigherstrokerisk(OR0.28;95%CI0.1–0.85).Sincetheselenopro-teinPconcentrationdependsontheseleniumstatus,itcanbeconcludedthatthemarkedlylowerserumseleniumconcentrationsinEuroperesultinlowerselenoproteinPlevels.Thereforethequestionmustbeposedwhetheraselenium-deficientdietpresentsanadditionalriskfactorapartfromhypertension,smokingandhypercholesterolemiaforstroke.
SignificantlylowerserumseleniumandselenoproteinPconcentrationsinstrokepatients
Stroke Control p value
Selenium in serum [µg/l] 105.2±19.6 116.5±16.6 0.054
SelenoproteinP[µg/l] 54.5±8.69 63.0±9.18 0.006
Modifiedaccordingto:KoyamaHetal.NutrRes.2009Feb;29(2):94-9.Depressed serumselenoproteinP:possiblenewpredicatorofincreasedriskforcerebrovascularevents.
Table 2
SELENIUM STATUS AND SELENOPROTEIN ACTIVITY30
Stroke patients show significantlydecreased
selenium values
1. ZimmermannCetal.EurNeurol.2004;51(3):157-61.Antioxidantstatusinacutestrokepatientsandpatientsat stroke risk.
2. KoyamaHetal.NutrRes.2009Feb;29(2):94-9.DepressedserumselenoproteinP:possiblenewpredicatorofincreasedriskforcerebrovascularevents.
3. OsterO,SchmiedelG,PrellwitzW.BiolTraceElemRes.1988Jan-Apr;15:23-45.Theorgandistributionof selenium in German adults.
4. SteinbrennerH,SiesH.ArchBiochemBiophys.2013Aug15;536(2):152-7.Selenium homeostasis and antioxidantselenoproteinsinbrain:implicationsfordisordersinthecentralnervoussystem.
5. BuckmanTD,SutphinMS,EckhertCD.BiochimBiophysActa.1993May13;1163(2):176-84.Acomparisonoftheeffectsofdietaryseleniumonselenoproteinexpressioninratbrainandliver.
6. ChenJ,BerryMJ.JNeurochem.2003Jul;86(1):1-12.Seleniumandselenoproteinsinthebrainandbraindiseases.
7. HiratoJetal.ActaNeuropathol.2003Sep;106(3):234-42.Encephalopathyinmegacystis-microcolon-intestinalhypoperistalsissyndromepatientsonlong-termtotalparenteralnutritionpossiblyduetoseleniumdeficiency.
8. AgamyOetal.AmJHumGenet.2010Oct8;87(4):538-44.Mutationsdisruptingselenocysteineformationcauseprogressivecerebello-cerebralatrophy.
9. CrackPJetal.JNeurochem.2001Sep;78(6):1389-99.Increasedinfarctsizeandexacerbatedapoptosisintheglutathioneperoxidase-1(Gpx-1)knockoutmousebraininresponsetoischemia/reperfusioninjury.
10. IshibashiNetal.BrainResMolBrainRes.2002Dec30;109(1-2):34-44.Glutathioneperoxidaseinhibitscelldeathandglialactivationfollowingexperimentalstroke.
11. YantLJetal.FreeRadicBiolMed.2003Feb15;34(4):496-502.TheselenoproteinGPX4isessentialformousedevelopmentandprotectsfromradiationand oxidative damage insults.
12. SavaskanNEetal.BiolChem.2007Oct;388(10):1007-17.Molecularbiologyofglutathioneperoxidase4:fromgenomicstructuretodevelopmentalexpressionandneuralfunction.
13. BellingerFPetal.MolNeurodegener.2011Jan21;6(1):8.GlutathionePeroxidase4isassociatedwithNeuromelanininSubstantiaNigraandDystrophicAxonsinPutamenofParkinson’sbrain.
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15. DringenR,PawlowskiPG,HirrlingerJ.JNeurosciRes.2005Jan1-15;79(1-2):157-65.Peroxidedetoxificationbybraincells.
16. BennerMJetal.PhysiolGenomics.2013Aug1;45(15):653-66.Sex-specifictranscriptionalresponsesofthezebrafish(Daniorerio)brainselenoproteometoacutesodiumselenitesupplementation.
17. JeeMKetal.Brain.2012Apr;135(Pt4):1237-52.MicroRNA486isapotentiallynoveltargetforthetreatmentofspinalcordinjury.
18. BurkRF,HillKE,ReadR,BellewT.AmJPhysiol.1991Jul;261(1Pt1):E26-30.Response of rat selenoproteinPtoseleniumadministrationandfate of its selenium.
19. SchomburgLetal.BiochemJ.2003Mar1;370(Pt2): 397-402.GenedisruptiondisclosesroleofselenoproteinPinseleniumdeliverytotargettissues.
20. HillKEetal.JBiolChem.2003Apr18;278(16):13640-6.DeletionofselenoproteinPaltersdistributionof selenium in the mouse.
21. HillKEetal.JNutr.2004Jan;134(1):157-61.NeurologicaldysfunctionoccursinmicewithtargeteddeletionoftheselenoproteinPgene.
22. Raman AV et al. Genes Brain Behav. 2012 Jul; 11(5):601-13.AbsenceofselenoproteinPbutnotselenocysteinelyaseresultsinsevereneurologicaldysfunction.
23. SavaskanNEetal.FASEBJ.2003Jan;17(1):112-4. Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
24. MehtaSLetal.BMCNeurosci.2012Jul9;13:79.Seleniumpreservesmitochondrialfunction,stimulatesmitochondrialbiogenesis,andreducesinfarctvolumeafterfocalcerebralischemia.
25. YousufSetal.BrainRes.2007May25;1147:218-25.Seleniumplaysamodulatoryroleagainstcerebralischemia-inducedneuronaldamageinrathippocampus.
26. HughesDJetal.IntJCancer.2015Mar1;136(5):1149-61.SeleniumstatusisassociatedwithcolorectalcancerriskintheEuropeanprospectiveinvestigationofcancerandnutritioncohort.
27. FiebichBLetal.FrontCellNeurosci.2014Sep1;8:260.Thetwo-hithypothesisforneuroinflammation:roleofexogenousATPinmodulatinginflammationinthebrain.
32 ATTACHMENT
Selenium in guidelines
Clinicalnutritioninintensivecare/inrisksituations*
Prematurebabies
Infantswithlowbirth
wei
ght
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Adu
lts
Bur
n pa
tient
s
Renalinsufficiency
Cirr
hosi
s
Adi
pose
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ient
s w
ith
previousbariatricsurgery
ClinicalNutritioninCriticalCareMedicineS2k-GuidelineoftheDGEM [A] ×ClinicalNutritioninSurgeryS3-GuidelineoftheDGEM [B] × ×EnteralandParenteralNutrition inPatientswithKidneyDiseaseS1-GuidelineoftheDGEM [C] ×ClinicalNutritionintheGastroenterology(Part1)–LiverS3-GuidelineoftheDGEM [D] ×ParenteralNutritioninPaediatricsS3-GuidelineoftheDGEM [E] × ×ESPEN/ESPGHANGuidelines onpaediatricparenteralnutrition[F] ×ESPENGuidelinesonParenteralNutrition:IntensiveCare [G] ×ESPENendorsedrecommendations:Nutritionaltherapyinmajorburns [H] ×ASPENGuidelines intheAdultCriticallyIllPatient [I] × × ×*Thistableprovidesanoverview.Pleaserefertotherespectiveguidelinefordetailedinformationondosage,applicationandconditionsofuse.
[A] Elke G et al. AktuelErnahrungsmed2018;43:341-408.[B] Weimann A et al. AktuelErnahrungsmed2013;38:e155-e197.[C] Druml W et al. AktuelErnahrungsmed2015;40:21-37.[D] PlauthMetal.AktuelErnahrungsmed2014;39:e1-e42.[E] JochumFetal.AktuelleErnährungsmedizin2014;39;e99-e147.
[F] KoletzkoBetal.JPediatrGastroenterolNutr.2005Nov; 41Suppl2:S1-87.
[G] SingerPetal.ClinNutr.2018Sep29.pii:S0261-5614(18)32432-4.[H] RousseauAFetal.ClinNutr.2013Aug;32(4):497-502.[I] McClaveSAetal.JPENJParenterEnteralNutr.2016Feb;40(2):
159-211.
33ATTACHMENT
Productsforinjectiontherapy
selenase® 100 µg pro injectione
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selenase® T pro injectione
500μgselenium in 10 ml solution for injection
2,10,30(3×10)and50(5×10)glassvials
1.000μgselenium in 20 ml solution for injection
2,10(N2),30(3×10)und50(5×10)glassvials
Activesubstance:Sodiumselenitepentahydrate.Prescriptiononly
selenase® 50 Mikrogramm Injektionslösung*
50μgselenium in 1 ml solutionforinjection
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selenase®
Active substance: Sodium selenite pentahydrate. selenase® 100 µg pro injectione, selenase® T pro injectione, selenase® 50 Mikrogramm Injektionslösung: 50 µg selenium per ml. Indications: selenase® 100 µg pro injectione, selenase® T pro injectione, selenase® 50 Mikrogramm Injektionslösung: Confirmed selenium deficiency that cannot be corrected by diet. Selenium deficiency can occur in conditions of maldigestion or malab-sorption, as well as in malnutrition (e.g. total parenteral nutrition). Composition: selenase® 100 µg pro injectione: 1 ampoule of 2 ml solution for injection contains: 0.333 mg sodium selenite pentahydrate, corresponding to 100 µg (micrograms) selenium. selenase® T pro injectione: 1 injection vial of 10 ml / 20 ml solution for injection contains: 1.67 mg / 3.33 mg sodium selenite pentahydrate, corresponding to 500 µg / 1000 µg (micrograms) selenium. selenase® 50 Mikrogramm Injektionslösung: 1 ampoule of 1 ml solution for injection contains as active substance 0.167 mg sodium selenite pentahydrate corresponding to 50 µg selenium in an 0.9 % aqueous NaCl-solution. Excipients: Sodium chloride, hydrochloric acid, water for injections. Contra-indications: Selenium poisoning. Undesirable effects: None known to date if the medicinal product is administered according to prescription. For selenase® 100 µg pro injectione, selenase® T pro injectione: General disorders and administration site conditions: Frequency not known (cannot be estimated from the available data): after intramuscular administration local pain at the site of administration has been reported. Form of administration, size of packages: selenase® 100 µg pro injectione: 10 or 50 ampoules of 2 ml solution for injection. selenase® T pro injectione: 2 or 10 injection vials of 10 ml solution for injection, hospital-size pack 30 (3 × 10) or 50 (5 × 10) injection vials of 10 ml solution for injection, 2 or 10 injection vials of 20 ml solution for injection, hospital-size pack 30 (3 × 10) or 50 (5 × 10) injection vials of 20 ml solution for injection. selenase® 50 Mikrogramm Injektionslösung: 10 and 50 ampoules respectively of 1 ml solution for injection. selenase® 100 µg pro injectione, selenase® T pro injectione: Subject to prescription. selenase® 50 Mikrogramm Injektionslösung: Subject to sale in pharmacies. 09/17 e
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