Behavioral Effects of Gangliosides: Anatomical Considerationsdownloads.hindawi.com/journals/np/1992/959785.pdf · Behavioral Effects of Gangliosides: Anatomical Considerations DwaineF.Emerich

Behavioral Effects of Gangliosides: Anatomical Considerations

Dwaine F. Emerich

Cellular Transplants, Inc.,Four Richmond Square, Providence, R102906

ABSTRACT

Gangliosides are endogenous sialic acidcontaining glycospingolipids which are highlyconcentrated in the central nervous system.Although they were first characterized over 40years ago, the function(s) played by this uniqueclass of lipids remain largely unknown.Gangliosides have been suggested to play aprominent role in both normal and abnormaldevelopmental processes. In addition, severallines of convergent evidence have indicated thatgangliosides exert pronounced trophic effectsfollowing damage to peripheral and centralnerves. Gangliosides have been shown to (1)enhance cell survival and outgrowth in culturedand developing neurons; (2) promote theregeneration of damaged peripheral and centralnerves, and (3) facilitate behavioral recovery byaltering the pattern, extent and persistence of thebiochemical, morphological and behavioralchanges induced by neural trauma. Little isknown, however, concerning the neurobiologicalmechanisms which subserve the behavioralprotection afforded by ganglioside treatment.This review focuses on the evidence suggestingthat gangliosides mediate functional recovery byminimizing primary or secondary cell loss orpromoting the regeneration or sprouting ofdamaged central nerves subsequent to injury.An understanding of the mechanisms by whichgangliosides produce their effects may lead to

Reprint address:Dr. Dwaine F. EmerichCellular Transplants, Inc.Four Richmond SquareProvidence, RI 02906USA

the development of more efficacious and rationalprimary or adjunct pharmacological treatmentsfor central nervous system disorders.

KEYWORDS

gangliosides, recovery of function,trophic factors, regeneration.

sprouting,

INTRODUCTION

One of the major goals of neuroscience is tounderstand and treat brain disorders. Despitetechnical and conceptual advances in theneurosciences we still face fundamentalquestions in neurology. Among the mostproblematic neurological disorders are thoseassociated with the degeneration of brainneurons. Neurodegenerative diseases, strokesand penetrating wounds all produce uniqueconstellations of behavioral symptoms that resultfrom the destruction of specific neuronalpopulations. Although research is beginning toreveal the pathophysio!ogy and molecularbiology of these disorders there remains a widegap between our understanding of the substratesof these diseases and our ability to prevent ortreat them.

Traditional approaches to the treatment ofacute and more chronic neurological disorderstypically produce very limited functionalrecovery and may even produce deleterious sideeffects. Even in cases where some degree offunctional recovery occurs, residual deficitstypically continue to compromise the individuals’quality of life/51L Based on the limited efficacyof current treatment modalities it is imperativeto develop treatments which limit the extent and

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2 DWAINE F. EMERICH

persistence of neural trauma and promotefunctional recovery.

Gangliosides are sialic acid containingglycospingolipids which are highly concentratedin neuronal membranes /40,45,65,66/. Theselarge, complex lipids are typically associated withthe outer surface of the neuronal membrane andconsist of a hydrophobic spingosine and stericacid complex inserted into the neuronalmembrane and a hydrophilic component con-taining sialic acid residues and a variety ofcarbohydrates which protrude towards theextracellular fluid. Although over 70 differentforms of gangliosides /96/ have been identified,most investigators have focused on the mono-sialoganglioside GM1 because of its demon-strated in vivo and in vitro efficacy as a trophicagent.

The location of gangliosides on the outerportion of the neuronal membrane has led to thespeculation that these molecules play a role incell surface events such as cell to cell recognition,synaptic transmission and receptor-ligand func-tions. Morphological, developmental, biochemi-cal and behavioral studies have shown thatgangliosides participate in a variety of neuro-biological functions related to the maturationand repair of neural tissue. For example, thereare pronounced changes in ganglioside concen-trations and distribution during synaptogenesisand central nervous system (CNS) maturation/29,59/. In addition, developmental disorderswhich result from impairments in the meta-bolism of gangliosides (e.g., Tay Sachs disease)are characterized by anomalous patterns ofneuronal differentiation and synaptogenesis aswell as progressive cognitive deterioration/85,86/. Moreover, administration of antibodiesto GM1 ganglioside to developing animalsproduces permanent alterations in the extent ofsynaptogenesis and myelination of nervous tissuetogether with deficits in learning performance/59/. In contrast, exogenously administeredgangliosides increase cell survival and enhanceneurite outgrowth when added to cultures ofdeveloping neurons /12,26,28,38,73/, promoteregeneration of damaged central and peripheralnerves /4,43-45/, and facilitate behavioralrecovery by altering the pattern, extent and

persistence of the biochemical, morphologicaland behavioral changes induced by neuraltrauma /16,17,20,30,32,34,35,37,82,83,89,92-97,115,120/. Based upon these observations it hasbeen proposed that gangliosides may serve asuseful pharmacological agents for augmentingthe plasticity of the CNS and promoting func-tional recovery. Results such as those describedabove, coupled with the practical considerationsthat gangliosides are capable of crossing theblood-brain barrier/64,81,111/and produce noovert toxic side effects /52/, make gangliosidesparticularly attractive neurotrophic agents forthe treatment of CNS injury. Although severalstudies have documented the efficacy of ganglio-sides in a variety of animal models and humanconditions, the mechanism by which gangliosidesexert their beneficial effects has remainedelusive (see Table 1). The purpose of this articleis to review the possible anatomical mechanismsby which gangliosides might produce behavioralrecovery in various models of CNS injury.

EFFECTS OF GANGLIOSIDES ONDEVELOPMENTAND PERIPHERALNERVOUS

SYSTEM REGENERATION

The expression of gangliosides correlates withthe development of the CNS and has led to thesuggestion that gangliosides play a role in normalneuronal growth. Willinger /117/ reported thatthe expression of ganglioside GM1 was markedlyincreased on the neuronal membrane of differ-entiating cells. Moreover, Rosner /91/ demon-strated that increases in the concentrations of avariety of endogenous gangliosides paralleledcell migration and neuronal differentiation in theoptic lobes of the chicken. The differentialalterations in ganglioside concentrations duringdevelopment do not provide direct evidence fora causative role in specific developmentalphenomena. However, the abnormal neuronaldevelopment associated with disorders ofganglioside metabolism does suggest a directmodulatory role for gangliosides in neuronalgrowth. GM1 gangliosidosis results from adeficiency of the enzyme/3-galactosidase whichis responsible for the degradation of GM1. As a

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BEHAVIORAL EFFECTS OF GANGLIOSIDES 3

TABLE 1

EFFECTS OF GANGLIOSIDES ON BEHAVIORAL AND NEUROBIOLOGICAL RECOVERY

FOLLOWING CNS LESIONS

Species/Lesion

Ganglioside Anatomical/ Behavioral RefTreatment Neumchemical Results

Results

Rat peroneal

Rat sciatic

Rat fourthltunbar root

Rat sciaticnerve; alloxan-

Mix of GM1, GDla, Enhanced neuromuscular 13GDlb, and GT1 control(50 mg/kg, IP)

Mix of GM1, GDla, Sprouting of moto- 44GDlb, and GT1 neurons(5 mg/kg, IP)

Mix from bovine Enhanced isometdc 102brain (50 mg/kg, IP) tension of plantaris

muscle

Mix of GM1, GDla,GDlb and GTlb(10 mg/kg, IP)

Ameliorated loss ofaxonal transport 70

Rat sciatic Mix of GM1, GD1a,nerve; diabetic GDlb, and GTlbpednextro- (20 mg/kg, SC)pathy

Rat; vinblastine- GM1 and/or NGFinduc sym- (30 and 1 mg/kg, SC)pathectomy

Rat ventro- Mix of GM1, GDla,medial septal GDlb, and GT1nucleus (50 mg/kg, IP)

Rat septal GM1 (30 mg/kg, IP)nucleus

Rat dorsalhippocampus

GM1 (30 mg/kg, IM)

Rat dorsalhippocampus

GM1 (30 mg/kg, IP)

Rat hippo-campus/neocortex

GM1 (30 mg/kg, IP)

Rat entorhinalcortex

Mix from bovinebrain (50 mg/kg, IM)

Improvement of nerveconduction

Reduced NE loss

Promoted recovery ofChAT and AChE

Decr emotionality 84

Enhanced recovery of ACHE,ChAT and 5-HT

Enhanced 5-HT uptake

Enhanced ChAT activity

Promoted recovery ofTo maze alternation

108

117

124

46

61

104

57

cont.

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4 DWAINE F. EMERICH

Table I (cont.)

Species/ GangliosideLesion Treatment

Rat entorhinalc,oftex

Mix of GM1, GDla,GDlb, and GT1(30 mg/kg, IM)

Rat dentate GM1 (30 mg/kg, IP)gyms

Rat dentate GM1 (30 mg/kg, IP)gyms

Rat dentate GM1 or AGF2gyms (15 and 10 mg/kg IP)

Rat hippo-campus

Rat nucleusbasalis

Rat nucleusbasalis

GM1 (15 mg/kg, IP)

GM1 (30 mg/kg, IP)

GM1 (5 mg/kg, ICV)

Rat septalnucleus

Rat septalnucleus

Rat nucleusbasalis

AGF2 (10 mg/kg, IP)

AGF2 (10 mg/kg, IP)

GM1 (10 mg/kg, IM)

Rat striatum GM1 (10, 30, or 50mg/kg, IP)

Rat striatum GM1 (30 mg/kg, IP)

Rat striatum GM1 or AGF2(30 mg/kg IP)

Rat substantianigra

GM1 (30 mg/kg, IP)

Rat nigrostriatal GM1 (30 mg/kg, IP)pathway

Ratnigrostriatal GM1 or AGF2pathway (30 mg/kg, IP)

Rat striatum GM1 (30 mg/kg, IP)

Anatomical/NeurochcmicalResults

Decreasedting

BehavioralResults

Rhyigraffivity

No reduction of cell loss Promoted recovery ofhyperactivity and pharm-acological sensitivity

No reduction of cell loss Increased ODC activityon c,ontralateral side

No reduction of cell loss Induced recovery ofT-maze performance

Prevent loss of ChAT andHAChU

Prevent cholinergic cellloss

Prevent decrease in ChAT Promoted recovery ofpassive avoidance andwater maze performaw

Rd

36

120

119

32

31

Induce recovery of Partial recovery of radial 34ChAT arm maze task

Prevent loss of ChAT Prevented hyperactivity 35and HAChU and cognitive deficits

Reduc loss of AChE Reduced mortality 69and ChAT

Reduced loss of ChAT 68andGAD

Reduc anterograde 97cell loss

Regeneration of nigro- 4striatal DA system

Reduced rotational beh- 94avior

116

Reduced rotational beh- 115avior

Reduced retrograde cell loss

Induced recovery ofTH

Promoted recovery of 93cognitive behavior cont.

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BEHAVIORAL EFFECTS OF OANGLIOSIDES S

Table I (cont.)

Species/ GangliosidLesion Treaunent

Anatomical/NeumchemicalResults

BehavioralResults

GM1 (30 mg/kg, IP)

Mouse sciatic Mix of GM1, GDla,nerve; diabetic GDlb, GT1periphe neuro- ( or 0 mg/kg, IP)pathy

Promoted recovery ofaxonal flow

76

Mouse periph-eral neumpathy

Mouse sub-smntia nigra(IVW’IP)

Mix of GMI, GDIa,GDIb, GTI(20 mg/kg, SC)

GMI or AGF2(30or 10 mg/kg, IP)

Infiberfing

Produced recovery ofDADOPAC

109

47

Mouse sub-sumtia nigra

Hamster sup-erior colliculus

Human stroke

GM1 (30 mg/kg, IP)

OM1 (30 mg/kg, IP)

GMI (20 mg, IM)

GM1 (40 mg, IM)

Human diabetic Mix of GM1, GDla,lwalmy GD1b, GT1b

(40 rag, IM)

Human idio- Mix of GM1, GDla,pathic facial GDlb, GTlbparalysis (20 mg, IM)

Enhanced sprouting ofretinotectal fibers

121

98

Prodtr,ed neurologicalimprovement

Enhanced neurophysio-logical and clinicalrecovery

Prodwaxl recovery of sen- 53sory perception of lowerextremeties

Complete recovery 54

Human GM1 (100 mg, IM) No improvement on cog- 3Alzheimex’s nitive or psychosocial

Human Mix of GM1, GDla Improved visual fieldretinitis GDlb, GTlb awand elecm3retino-pigmintosa (40 mg, IM) graphic responses

72

NOT: AChE acetylcholine esterase; ChAT choline acctyltmnsferase; DA dopamine; DOPAC 3,4,-dihydroxyphenylacctic acid; GAD glutamic acid decarboxylasc; HAChU high affinity choline uptake;MFrP 1-methyl-4-phenyl-l,2,3,6-tewahydropyridine, NE norepinephrine; NGF nerve growth factor;ODC ffi ornithine decarboxylase; IP intraperitoneal; SC subcutaneous; IM intramuscular; ICVinwaventricular.

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6 DWAINE F. EMERICH

result of this deficiency, meganeurites, charac-terized by multiple neuritic processes, neurites,and spines develop throughout the nervoussystem/85,86/. Since this pattern of cell growth istypically observed only during early stages ofdevelopment, these results indicate that anabnormal accumulation of gangliosides has adirect influence on the subsequent growth ofneurons.

lumerous in vitro experiments havedemonstrated that exogenous gangliosides alterthe morphological characteristics of culturedneurons /12,26,28,38,73,125/. Gangliosidespromote neuritogenesis in a variety of cell lines,with certain cells responding only to specificspecies of gangliosides. For instance, Carine etal. /15/ reported that GM1, but not GDla,enhanced neuritogenesis in S20Y murine neuro-blastoma cells. Similarly, the selectivity ofafferent connections in tetrodotoxin-treatedspinal cord explants is dependent on the speciesof gangliosides used/6/. Mixed bovine ganglio-side treatments produced a selective afferentconnectivity in these culture preparations whileGM1 alone produced a nonselective connecti-vity. These studies indicated that the exogenousaddition of gangliosides enhances the outgrowthof cultured neurons but that this outgrowth isdependent on the molecular form of the ganglio-side used. Since the distribution of gangliosidesin the nervous system is variable, it is conceivablethat gangliosides normally play a role inmediating specific forms of neuronal connectivityand that the extent of functional recoveryafforded by gangliosides is a function of preciseand subtle anatomical changes.

Ceccarelli and colleagues /18/ initiallyreported that the exogenous administration ofgangliosides promoted sprouting in theperipheral nervous system (PNS). Following apre- and postganglionic anastomosis of thesuperior cervical ganglion in cats, dailyadministration of gangliosides resulted in acomplete recovery from paralysis together withnormal pupillary and nictitating membranefunction. Since animals typically exhibit a partialrecovery from this surgery as a result ofregenerating axons reinnervating the cervicalganglion it was concluded that the gangliosides

had promoted the regeneration of the axoto-mized fibers. Support for the assumption ofregeneration came from visualization ofincreased eatecholaminergic histofluorescence inthe cervical ganglion following the anastomosis.Since these initial studies, several laboratorieshave confirmed that gangliosides promote theregeneration and sprouting of damagedperipheral nerves and muscle/13,44,45,56,60/.

GANGLIOSIDE-INDUCED REGENERATIONANDSPROUTING FOLLOWING NEURAL INJURY

Septohippoeampal cholinergic system

Given that gangliosides could markedlypotentiate the regenerative response ofperipheral nerves, Oderfeld-Nowak andcolleagues /77-80/ investigated the effects ofganglioside treatment on the sprouting responsewhich results from partial denervation of thecholinergic input to the hippocampus (HPC).Following damage to the septum, there is aninitial decrease in the enzymes acetyl-cholinesterase (ACHE) and choline acetyl-transferase (CHAT) in the HPC which is thenfollowed by a progressive recovery of enzymaticactivity over the next several months/75,79/. Therecovery of neurochemical activity correlateswith the appearance of newly formed synapticcontacts in the HPC and is considered to be anaccurate marker of sprouting of survivinghippocampal afferents. Following electro-coagulation lesions, a mixture of gangliosidesaccelerated the recovery of AChE and ChATactivity in the HPC/77,79,80/. While the initialdecline in enzymatic activity was equivalentregardless of whether the animals receivedgangliosides or not, gangliosides produced asignificant increase in AChE and ChAT activitycompared to controls at both 18 and 50 dayspost-surgery. These same investigators reportedthat ganglioside GM1 promoted sproutingfollowing ablations of the entorhinal cortex/78/.At 3 weeks following surgery, GM1 enhanced therecovery of AChE and ChAT activity in the HPCindicating an enhancement of the sproutingresponse of the septohippocampal pathway.


Given that gangliosides appeared to enhancethe plasticity of the septohippocampal choli-nergic pathway, investigators examined thebehavioral consequences of this acceleratedresponse. Karpiak /57/ examined the perfor-mance of rats on a spatial alternation taskfollowing unilateral lesions of the entorhinalcortex. Animals receiving daily injections ofGM1 made significantly fewer errors on the firstpostoperative day compared to lesioned animalstrot receiving ganglioside treatment. Because thisreduction in the lesion-induced behavioraldeficits preceded the period of time considerednecessary for reinnervation to begin, theseresults were interpreted as indicating that GM1exerted a protective rather than regenerativeeffect. To evaluate this possibility Fass andRamirez /36/ bilaterally lesioned the entorhinalcortex producing increases in open-field activitywhich typically recover over a two week period.Animals treated with GM1 were less active thanlesioned animals receiving saline treatment asearly as two days post-surgery suggesting that thebehavioral protection was independent ofalterations in the sprouting response. Fur-thermore, a reduction in the density of AChEstaining was observed in the dentate gyrus ofanimals treated with gangliosides indicating thatGM1 might have actually suppressed thesprouting response. The interpretation of theseresults was further complicated by a comparisonbetween the behavioral and histological analysiswhich revealed that there was no obviousrelationship between the recovery of thebehavioral impairments and the alterations inAChE staining. Poplawsky and Isaacson /84/further demonstrated that ganglioside treatmentdecreased the hyper-emotionality followingseptal lesions. Again, these changes wereobserved within two days following surgery,making it unlikely that structural changes, suchas sprouting, accounted for the observedbehavioral effects.

More recently, Emerich and Walsh /34/examined the effects of ganglioside AGF2 (theinternal ester of GM1) on the behavioral andneurochemical consequences of bilateralinjections of ethylcholine mustard aziridiniumion (AF64A) into the lateral ventricles of rats.

AF64A produced an impairment on both astandard radial arm maze (RAM) task and whena 1 hour delay was imposed between the fourthand fifth arm choices. Although the initialimpairment was equivalent regardless of whetherthe AF64A-treated animals received AGF2 orsaline, the AGF2-treated rats recovered on thestandard RAM task within 4 weeks but werepermanently impaired on the delay version ofthe task. Neurochemical analysis revealed thatAGF2 enhanced ChAT activity in thehippocampus at 20, but not 2 or 11 weeksfollowing surgery. Cell counts of cholinergicneurons in the medial septum revealed thatAGF2 did not reduce the extent of neuronal loss.As in the study by Fass and Ramirez /36/, thesedata indicated that AGF2 might have enhancedthe sprouting of cholinergic terminals followingthe initial insult, but that the behavioral recoveryexhibited by these animals was incomplete andunrelated to that sprouting.

It appears, then, that there is no clearevidence which directly links ganglioside-inducedsprouting to behavioral recovery followingdamage to central cholinergic systems.Gangliosides have been shown to influencebehavioral recovery at times too early to beaccounted for by structural changes or at timesremoved from the occurrence of such changes/34,36,57,84/. The interpretation of therelationship of sprouting to behavioral recoveryis also complicated by the methods used to assesssprouting. Changes in enzyme levels do notnecessarily reflect an effect of ganglioside onsprouting. Rather gangliosides could bemodulating a lesion-induced up-regulation oftransmitter biosynthesis and release. Ganglio-sides could also directly stimulate the activity ofthe enzymes involved in the synthesis ofacetylcholine (ACh). Cuello and colleagues/20/found that GM1 significantly increased ChATactivity in the nucleus basalis in sham-operatedrats. In addition, Hefti et al. /49/ reported that aganglioside mixture directly increased ChATactivity in cultures of dissociated fetal septalneurons without altering fiber outgrowth ofthose cholinergic neurons. Accordingly, ganglio-sides might enhance ChAT activity followingseptal lesions by increasing the activity of this

8 DWAINE F. EMERICH

enzyme in surviving neurons. However, en-hanced sprouting and direct stimulation ofChAT activity need not be mutually exclusiveevents and might act in a coordinated manner tocreate a more conducive neural environment forthe initiation of structural repair processes whichpromote functional recovery.

Nigrostriatal dopamine system

The nigrostriatal dopamine system also lendsitself to an analysis of the correlation betweenbehavioral recovery and regeneration/reinnervation processes. Transections of thenigrostriatal tract result in a marked reduction intyrosine hydroxylase (TH) and homovanillic acid(HVA) content in the denervated caudate.Behaviorally, rats with unilateral lesions exhibit astereotyped rotational behavior when challengedwith dopaminergic agonists such as apomorphineor amphetamine. Toffano and colleagues/113-115/ reported that gangliosides reduced thenumber of apomorphine-induced rotations at 14and 30, but not 8 days, following a unilateralhemitransection of the nigrostriatal pathway. Itwas also reported that TH levels in saline-treated controls were 50% of normal whileanimals receiving gangliosides exhibited only a20% decrease in TH. Increased levels of HVAand TH-immunofluorescence substantiated theganglioside related increase in dopaminergicactivity at the later, but not earlier, time points.Since this time course coincided with thatexpected for terminal reinnervation of thestriatum, it was concluded that gangliosidesenhanced behavioral recovery through increasedsprouting of dopaminergic fibers. However, theinterpretation of these studies are also subject tothe possibility that gangliosides simply increasedHVA and TH activity through a compensatoryincrease in neurotransmitter synthesis andrelease. Following damage, survivingdopaminergic neurons increase their rate ofsynthesis and metabolic activity. Gangliosidetreatments might act to accelerate this process,thereby affording the animal some degree ofbehavioral recovery.

To address this issue more carefully, Sabel etal. /92,94/ injected HRP into the striatum

following transection of the nigrostriatalpathway. It was assumed that if GM1 gangliosidewas promoting sprouting then an increasednumber of HRP-positive cells should bevisualized within the substantia nigra. At post-operative day 3 there were no differences in thenumber of labeled cells between the saline andGMl-treated animals. However, at day 15 therewere significantly more labeled neurons in thoseanimals treated with GM1. While these resultsstrongly suggested that GM1 stimulatedreorganizational processes, these same processesdo not necessarily underlie behavioral recovery.In fact, a dear dissociation of behavioral andmorphological recovery was observed in thesestudies. While ganglioside-treated animalsexhibited decreases in rotational behavior asearly as two days following surgery, there wereno apparent differences in HRP-labeled cells inthe substantia nigra. Although these two indicesmay correlate at later time points, the proposedsprouting of dopaminergie fibers cannot accountfor this early behavioral recovery.

Other studies have failed to find a dearcorrelation between anatomieal/neuroehemiealand behavioral recovery following gangliosidetreatment. Sabel et al. /93/ reported thatgangliosides ameliorated the deficits in spatialalternation behavior following bilateralelectrolytic lesions of the eaudate nucleus. Uponhistological evaluation, it was revealed that therewere no differences in the number of neurons orglia adjacent to the lesion site or in thesubstantia nigra between those lesioned animalsreceiving gangliosides and those receivingvehicle control injections. While a protectiveeffect of gangliosides was not likely in thesestudies, the role of sprouting remains a possiblecontributor to the observed functional recovery.Dunbar et al. /30/ examined the effects ofgangliosides on rotational behavior, aphagia andadipsia following complete transeetions of thenigrostriatal pathway. Following total lesions,gangliosides were ineffective in reducingamphetamine-induced rotational behavior /30/.However, these same ganglioside-treatedanimals demonstrated a significant attenuationof the initial decrease in body weight. Togetherwith previous neuroehemieal studies, these data

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BEHAVIORAL EFFECTS OF GANOLIOSIDES 9

suggested that there may be a dissociationbetween functional and neurobiological recoveryin ganglioside-treated animals.

Other systems

The ability of gangliosides to promotesprouting has been evaluated in a variety ofother neural regions. Kojima et al. /62/ infused 6-hydroxydopamine (6-OHDA) into the cerebralcortex via an osmotic minipump. Fluorescenthistochemistry and neurochemical analysisrevealed a significant loss of fluorescent nerveterminals and norepinephrine (NE) levels in thecortex within 3-7 days. Within 5 weeks there wasa reappearance of nerve terminals within thedamaged region. Treatment with gangliosideGM1 significantly elevated NE levels at 7 and 14days following 6-OHDA with no effect on theinitial loss of NE terminals.

Jonsson et al. /55/ reported that GM1restored serotonin (5-HT)levels in the cortexfollowing systemic injections of the serotonergicneurotoxin 5,7-DHT. Again, GM1 had no effecton the initial loss of 5-HT terminals, rather theeffects were observed to occur following theinitial result.

Fujito et al. /41,42/ conducted a series ofexperiments which suggested that gangliosidespromoted sprouting in the red nucleus of kittens.Following neocortical damage, the probability ofproducing excitatory postsynaptic potentials(EPSPs) in the red nucleus decreased to approx-imately 20%. Gradually, EPSPs reappeared, in-dicating a sprouting response of the previouslydegenerating cortical afferents. Placement of asponge containing a crude ganglioside extractinto the wound cavity resulted in an increasedprobability of inducing EPSPs in the red nucleusat 3 weeks post-lesion. These data indicated thatgangliosides promoted a sprouting response andthat this response had a functional consequence(i.e., production of EPSPs).

Other investigators have suggested thatgangliosides promote sprouting in the spinalcord following transections /10,19/ and in thehamster visual system following lesions of thesuperior colliculus/98/.

GANGLIOSIDE-INDUCED PREVENTION OFNEURONALDEGENERATION

The foregoing discussion strongly suggeststhat ganglioside-induced enhancement ofsprouting does not necessarily account for thepromotion of functional recovery. Given thatbehavioral recovery processes have beenfrequently reported to occur relatively soonfollowing injury (i.e., at times prior to theinitiation of sprouting), a more parsimoniousexplanation for these effects might be that theylimit the extent of neuronal damage producedimmediately following surgery. The followingsection reviews the evidence for this possibilityand discusses possible biological mechanismsunderlying this prophylactic effect.

Nucleus basalis-cortical cholinergic system

Following lesions of the magnocellular nuclei,high affinity choline uptake (HAChU) andChAT activity is decreased by approximately50% in the frontal cortex. Treatment with GM1prevented the decreases in HAChU in thefrontal and parietal cortex as early as 4 daysfollowing surgery/82/. Because of this early timecourse of recovery, the sparing of HAChUcannot be accounted for by collateral sprouting.Following unilateral cortical lesions, GM1 alsoprevented the retrograde cell atrophy in thenucleus basalis /20/. Accompanying thisattenuation was a significant protection againstthe loss of ChAT activity in this same region.Unfortunately, a time course analysis was notperformed to determine whether GM1 actuallyprevented or reversed the cell shrinkage.

Casamenti and colleagues/17/confirmed thatganglioside treatment not only prevents the lossof cortical cholinergic parameters followingdamage but also improves the rate of acquisitionof an active avoidance task. These behavioraleffects were observed during the initial stages ofbehavioral testing (4-7 days post-surgery) andruled out the possibility that collateral sproutingunderlay the observed alterations in cholinergicfunction. Rather, these results may beinterpreted as indicating that GM1 either

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prevented terminal degeneration or producedcompensatory increases in cholinergic enzymaticactivity at time points shortly following injury.The contention that exogenous gangliosideadministration attenuates the initialconsequences of damage to the magnocellularnuclei is supported by a recent study by Cuelloand colleagues/20/. These investigators reportedthat GM1 prevented the retrograde atrophy andloss of cholinergic neurons in the nucleus basalisfollowing cortical damage. Importantly, thiseffect was observed both following systemicadministration of GM1 and following theplacement of microencapsulated GM1 onto thedamaged cortical surface /71/. Elliott andcolleagues/31/examined the effects of GM1 onthe neurochemical and behavioral changesproduced by unilateral devascularizing lesions ofthe neocortex. Following surgery, animalsexhibited a series of behavioral alterations,including hyperactivity, motor uncoordination,impaired passive avoidance retention andreacquisition, and decreased retention of aMorris water maze task. Infusion of GM1directly into the lateral ventricles via minipumpsprevented the retrograde degeneration ofcholinergic nuclei in the nucleus basalis andenhanced the reacquisition of both the passiveavoidance and water maze task but had no effecton the hyperactivity or motor coordination tasks.

Septohippocampal cholinergic system

Ganglioside-induced prevention ofcholinergic cell loss has also been reportedfollowing damage to the septohippocampalcholinergic system. DiParte et al. /27/reportedthat the intraventricular injection of vincristinedecreased ChAT and HAChU in the HPC andthat these decreases were prevented by priortreatment with ganglioside GM1. Sofroniew et al./104/ further demonstrated that gangliosidesprevented the retrograde cell loss in the medialseptum and vertical limb of the diagonal bandfollowing hippocampal ablation.

To evaluate the ability of gangliosides toprevent damage to the septohippocampalcholinergic system and the associated behavioralconsequences, a series of studies using the

neurotoxin colchicine were conducted /33,35/.Intraventricular administration of colchicineproduced marked decreases in hippocampalChAT activity and HAChU levels withoutdamage to hippocampal granule cells which aresusceptible to direct administration of colchicine.Behaviorally, colchicine-treated animalsexhibited a pronounced hyperactivity andmarked cognitive deficits which were preventedby AGF2 administration. While previous studieshad indicated that gangliosides produced a taskdependent behavioral recovery /17,34/ therecovery in these studies was complete. Lesionedanimals receiving AGF2 were able to perform aradial arm maze task as well as controls, evenwhen a delay as long as four hours was imposedbetween the fourth and fifth arm choices.Neurochemical and anatomical analysesindicated that AGF2 prevented the decreases inhippocampal ChAT and HAChU as well as theloss of cholinergic neurons in the medial septum.These data clearly indicated that gangliosides arecapable of preventing the biochemical,anatomical and behavioral consequences ofneural damage.

Interestingly, ganglioside treatment appearedto exert a different profile of effects followingintradentate injections of colchicine. Followingintrahippocampal administration, colchicineproduced extensive decreases in the thickness ofboth the superior and inferior blades of thedentate gyrus and an associated retrogradedegeneration of cholinergic neurons in themedial septum /32,33/. GM1 administrationfacilitated the recovery of normal locomotoractivity, attenuated the impaired retention of apassive avoidance task and reduced thelterations in sensitivity to the motor stimulatingeffects of apomorphine and the analgesic effectsof morphine/118/. Furthermore, both GM1 andAGF2 facilitated recovery of working memory ina multiple component T-maze task /32/.However, quantitative analysis revealed that,despite the facilitative effects of gangliosidetreatment on behavior, there was no obviousreduction in the extent of colchicine-inducedgranule cells destruction or the retrogradedegeneration of cholinergic neurons in themedial septum.



In contrast to the failure to find anyanatomical correlate to the ganglioside-inducedbehavioral recovery following intrahippocampalcolchicine, biochemical evidence suggesting apossible protective effect of GM1 has beenobtained. Following intrahippocampal injectionsof colchicine, Walsh et al. /119/ examined theeffects of GM1 on the expression of ornithinedecarboxylase (ODC) activity in the HPC.Ornithine decarboxylase is the rate-limitingenzyme in the synthesis of the polyaminesputrescine, spermine, and spermidine and hasbeen suggested to provide a reflection of theextent of neural damage present. Followingunilateral injections of colchicine into thedentate gyms, ODC activity increased 8-fold inthe HPC. Prior treatment with GM1 gangliosidesignificantly reduced this response on theipsilateral side but enhanced the ODC responseon the contralateral side. These ganglioside-induced changes were independent of anyprotective action of GM1 on hippocampalmorphology. Since changes in ODC activity arecorrelated with the magnitude of neural damage,it appeared that GM1 may have altered some ofthe secondary consequences of hippocampaldamage.

The mechanism by which gangliosides exerttheir protective effects on cholinergic systems isunclear but may relate to the interaction ofgangliosides with endogenous neurotrophicfactors at or near the site of injury. Several linesof evidence indicate that gangliosides augmentendogenous biological responses that areinitiated by injury and subserve neuroplasticity. Itis well established that levels of endogenoustrophic factors increase following neural damage/74,75/. Furthermore, the early administration oftrophic agents, including nerve growth factor(NGF) and gangliosides, are effective inreducing both cell death and the behavioraldeficits associated with neural injury /21,22,27,31,35,50,63,107,122/. The typical increases ininjury mediated trophic factors may not besufficient to prevent the lesion-induced cell losswhich occurs immediately following injury, orthese increases may occur at a time subsequentto the majority of cell loss. The administration ofcompounds capable of interacting with

endogenous trophic factors or altering theresponse of neurons to the levels of endogenoustrophic factors may represent one method forminimizing injury related cell loss. Gangliosideshave been suggested to exert their trophic effectsby interacting with endogenous NGF. Thissuggestion is supported by several convergentlines of evidence: (1) gangliosides and NGFpromote cell survival and increase ChAT activityin the nucleus basalis in a synergistic mannerfollowing cortical damage /20/; (2) GM1potentiates the ability of NGF to prevent thedecreases in norepinephrine levels in the heart,spleen and kidneys following systemicadministration of vincristine /117/; (3) GM1initiates neurite outgrowth in fetal chick dorsalroot ganglionic cells and PC12 cells in a NGF-dependent manner/28,103/, and (4) the ability ofGM1 to prevent the loss of cholinergic neuronsin the nucleus basalis diminishes as the age of theanimal increases and the normal and lesion-induced levels of trophic factors decrease/107/.

Although the exact mechanism by whichgangliosides potentiate the actions of NGFremains unknown, it may relate to a modificationof membrane surface properties subsequent tothe incorporation of gangliosides into themembrane. Unfortunately Ferrari /39/ failed tofind increased binding of NGF to PC12 cellsfollowing ganglioside treatment. However,gangliosides could still conceivably modulate avariety of neuronal processes including surfacetransduction or specific NGF related post-translational events (see /22/ and /101/ forreviews).

Gangliosides may also alter axonal transportand in turn increase the availability of NGF orother trophic factors to deprived neurons.Gangliosides promote the formation ofmicrofilament networks in cultured neuro-blastoma cells/106/as well as stimulating tubulingene expression following transections of thenigrostriatal pathway /126/. By accelerating orpromoting the organization of cytoskeletalelements, gangliosides may enhance thetransport and subsequent availability of trophicfactors such as NGF under normal conditionsand following injury. The ability of gangliosidesto modulate the regeneration of damaged nerves

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by altering the axoplasmic transport ofmacromolecules has been investigated followingnerve crush of the optic nerve in goldfish.Following nerve crush, the optic nerveregenerates over a 2-4 week period in parallelwith increased visual acuity /23,24/. Sbaschnig-Agler et al. /100/reported an 8-fold increase inthe axonal transport of gangliosides followingcrush of the optic nerve. This increase wasevident within 8 days following surgery andpersisted for up to 25 days. In addition,intraocular injections of antibodies togangliosides inhibited the regeneration of theoptic nerve following nerve crush /105/. Dailyinjections of antiserum beginning 5 days prior tosurgery resulted in a 40% decrease in thedistance of axonal outgrowth measured 10 daysafter the crush. These data suggested thatgangliosides may play a role in neural outgrowthand regeneration by modulating the transport ofvarious macromolecules such as NGF.

Nigrostriatal dopamine system

As already mentioned, the evidencesupporting a role for gangliosides in mediatingbehavioral recovery via sprouting of survivingdopaminergic afferents is questionable. Severallines of evidence indicate that behavioralrecovery occurs at time points too early to beaccounted for by structural changes. On theother hand, there is evidence to suggest thatgangliosides may act to reduce the initialconsequences of damage to this system.

Within 2 weeks following a partialhemitransection of the nigrostriatal pathway,animals treated with gangliosides exhibit anattenuated decrease in TH activity. Toffano et al./116/ reported that this amelioration wasassociated with a ganglioside-induced reductionof the loss of dopamine neurons. Both the THand immunocytochemical indices necessarily usedopamine to evaluate cell number and theseresults could also be interpreted as indicatingthat gangliosides are simply increasingtransmitter synthesis.

In an attempt to evaluate more carefully thepossible protective effects of gangliosides, Sabel

et al. /97/used the Fink-Heimer technique toquantify the extent of anterograde degenerationin the substantia nigra following hemitransee-tions of the nigrostriatal pathway in the lefthemisphere and an electrolytic eaudate lesion inthe fight hemisphere. Seven days following thelesion, the animals treated with GM1 had signifi-cantly smaller areas of neuronal degeneration onthe side with the caudate lesion than thoseanimals treated with saline. In contrast, therewas no effect of ganglioside treatment on theside with the hemitranseetion. While GM1 hadno effect following the hemitransection in thesestudies, Raiteri and colleagues/88/reported thatAGF2 decreased the reduction of [3H]dopamineuptake into stfiatal synaptosomes five days fol-lowing surgery. Although not conclusive, thecombined anatomical and neuroehemieal datasuggest that gangliosides exert some protectiveeffect following damage to the nigrostriatalsystem.

The contention that gangliosides producebehavioral recovery by minimi_ng cell damage issupported by a study by Li et al./67/. Two daysfollowing unilateral nigrostfiatal transeetions,amphetamine-induced rotational behavior wasreduced by ganglioside treatment. The ganglio-side treatment also prevented the loss of striatalNa+,K+-ATPase activity typically observed fol-lowing damage. Two days following transection,the level of Na+,K+-ATPase was decreased 36%in lesioned animals but only 7% in lesionedanimals receiving gangliosides. Became in-creased Na+,K+-ATPase activity had been pre-viously shown to correlate with the extent ofedema, it was concluded that the gangliosideshad minimized the extent of edema and in turnpromoted functional recovery.

Ischemia

Karpiak and colleagues have used a model oftransient cerebral isehemia to investigate theeffects of gangliosides on behavioral recovery/58/. In particular, this model has been employedto evaluate the suggestion that gangliosidesproduce their effects through the induction ofdiscrete metabolic events immediately afterdamage. The most studied metabolic alterations

JOURNAL OFNEURALTRANSPLANTATION & PLASTICITY

BEHAVIORAL EFFECTS OF OANOLIOSIDES 13

concern the ability of gangliosides to reduce thedecrease in membrane Na+,K+-ATPase whichoccurs following cell damage. Gangliosidesproduced a 33% reduction in edema 48 hoursfollowing cortical damage in rats /58/. Thisreduction was accompanied by a significantattenuation of lesion-induced reduction inplasma Na/,K+-ATPase levels and paralleledenhanced cerebral blood flow, reduced celldamage, electrocorticographic alterations andneurological deficits/14/.

There have been a limited number of clinicalstudies examining the effects of gangliosides inhuman stroke patients. Bassi/7/reported thatpatients receiving gangliosides had a higher levelof neurological functioning than a similar groupof individuals treated with placebo. Likewise,Battistin /8/ demonstrated that gangliosidetreatment resulted in improved neurophysiolo-gical ratings in patients with cerebrovasculardisease. Importantly, the ganglioside treatmentin both these studies was effective even though itbegan at least 10 days following the initial lesion.Therefore, it may not be absolutely necessary toadminister gangliosides during the acute phaseof such an injury. Such a treatment may still beeffective during the subacute phase and mightactually exert a more powerful effect if givenearlier.

CONCLUSIONS

Gangliosides appear to be capable ofproducing potent behavioral recovery following avariety of CNS perturbations/16,17,20,30,32,34,35,82,89,92-97,113,115,120/. Gangliosides havebeen shown to reduce motor and cognitive defi-cits in laboratory animals as well as the clinicalsigns of neurological functioning in humans. Incontrast, only a small number of studies hasfailed to demonstrate a beneficial effect ofganglioside treatment /11,17,30,.34,84/. Impor-tantly, in those studies failing to show anysignificant improvement following gangliosidetreatment in humans, there have not been anydemonstrated deleterious effects. For instance,chronic administration (up to 12 months) ofGM1 ganglioside to Alzheimer’s patients did not

result in any neurological improvement but hadno toxic side effects either, demonstrating thelong-term safety of chronic ganglioside treatment/3/. Unfortunately, these investigators were notable to determine if the GM1 treatmentsignificantly slowed the progression of thedisease. Recent studies have suggested thatantibodies to GM1 are present in high levels inindividuals afflicted with Guillain Barresyndrome, suggesting that chronic administrationof gangliosides could contribute to thedevelopment of this disease/87,127/. However, arecent study failed to reveal antibody formationfollowing parenteral injection of gangliosides inAlzheimer patients/110/. Nevertheless, the pos-sibility of untoward side effects from gangliosidetreatment deserves serious attention prior tolarge scale clinical trials. The possibility of sideeffects further underscores the need to deter-mine the mechanism underlying ganglioside-induced recovery.

Several lines of evidence suggest thatgangliosides promote sprouting of CNS neuronsand that this sprouting response mediatesbehavioral recovery /92,93,113-115/. However,there are also numerous studies which seriouslyquestion this conclusion /34,36,57,84/. Most ofthe evidence of ganglioside-induced sprouting isbased on observations of increased transmitterlevels or their metabolites. Additionally,increased retrograde cell labeling has beenprovided as evidence of enhanced sprouting.These indices do not, however, provide directevidence of enhanced sprouting and could simplyreflect increased transmitter levels, enzymeactivity, axonal transport processes or a uniquecombination of these events. Future studiesusing electron microscopy, tract tracingtechniques, autoradiography, electrophysiologyand in vitro techniques are needed tosubstantiate ganglioside-induced sprouting.

Regardless of whether gangliosides doactually promote sprouting, it appears that this isnot always the basis of behavioral recovery.Functional recovery has been frequentlyreported prior to, or independent of, measuresindicative of sprouting /34,36,84/. Such adissociation suggests that events which precedesprouting may be the basis for some observed

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recovery. Although few studies have actuallydemonstrated neuronal sparing followingganglioside treatment, some have provideddirect evidence of a protective effect /20,35/.While either an enhancement of sprouting or aprophylactic effect of gangliosides is appealing,neither can account for all observed behavioralrecovery. It appears then that a variety offactors, including the type, location, and extentof the lesion, may affect the ability ofgangliosides to modulate behavioral recovery.Further complicating our understanding ofrecovery are questions concerning the effectivespecies of gangliosides for eliciting recovery fromvarious lesion types, as well as practicalconsiderations, including the doses, timing androute of administration and which portion ofganglioside molecule is responsible for anobserved effect. These considerations withhold-ing, gangliosides appear to be useful for treatinga variety of CNS injuries. Although not apanacea, answers to the above questions mayaccelerate our development of an efficacious andrational approach for using gangliosides or otherpharmacological treatments as primary oradjunct therapies in disorders of the CNS.

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Behavioral Effects of Gangliosides: Anatomical Considerationsdownloads.hindawi.com/journals/np/1992/959785.pdf · Behavioral Effects of Gangliosides: Anatomical Considerations DwaineF.Emerich