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Melanocortins, neural plasticity and aging
Prog.
Neuro-Psychopharmncol.
Printed
in Great
Britain.
6 Biol. Psychiot. All rights
1986.
Vol. 10. pp. 415426 Copyright
reserved.
MELANOCORTINS,
WILLeM
NEURAL PLASTICITY
0
0276-5646166 1986 Pergamon
$0.00 + .50 Journals Ltd.
AND AGING
HENDRIKGISPEN,ROBEFCC L. ISA?CSON,l,BERRYM. SPRUIJT andDAVIDDEWIED
Divisionof ~lecular Neurobiology, RudolfMagnus Institutefor Pharmcolcgy and Instituteof Mxhcular Biology,StateUniversityof U-&e&t Padualaan,CHUtrecht TheNetherlands %e partnmk of Psychologyand Center for NwrokehavioralSciences UniversityCenterat Binghamton Binghamton,NY U.S.A. (Finalform, February1986)
AbStiaCt
1. 2. 3. 4. 5. 6. 7.
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Intrcduction TrophicEffectsofhklamcortins RecoveryfranPeripheral Nerve Damage HippocampalPlasticity RecoveryfrcmBrainDamage BehavioralPlasticity Conclusions ~ferences
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Gispen,Willem Hendrik,F&ert L. Isaacson,Berry M. Spmijt and David de Wied: Mslanocortins, neuralplasticityand aging. Prog. Nemo-Psychophamacol.& Biol. Psychiat.,1986,g (3-5):415-426. 1. PeptidesderivedfranACHTand a-MSHarekncwntoexerktrophic influenceson peripheralandcentralnemous structures. :. we -related.braindiseasesmayinpartke relatedtoloss ofneuralplasticity. Melanocortins hqzove adaptionalabilitiesofthe nervoussystem. 4: Chronictreatmntwithmlanccortinsmycoun~act age-relatedbrainpathology. neural Keywords: ACIH, a-MSH,behavioralplasticity,brain aging,nerve regeneration, plasticity,neurotmphic effects. Abbreviations: pdrenocorticotropic honmm (ACTH),Calcim (Ca2+),Dzpmine receptor, type 2 (D2),ThousandDalton~aswe (kDa),mlamcyk-stirrailating w(s) (MSJ-0 rikonucleicacid (RNA),a-ml amcyte-stimulatinghorrmne(a-MSH),Serim(ser),Serotonin receptar, type 2 WI, Tyrosine kYd
415
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W. H.Gispen
1.
et al.
Induction
Inthepast25 yeam or so, trmmdominsighthasbsengaimdwithregardtothe functionsoftheIIelanccortins system activities.Variw disciplines w-Jwm3-u on Ilervms within~neuroscienceshaveindicatedaroleofthesepeptidesinbrainandbehaviar,and these investigations haveledtoaniqxessivenmberof functional, adaptivethat seem to be nodulatedby the malanocortins(DeWied and Jolles 1982). Ihe &z mechanisms inbrainandbehavior areoftendescribedintmmsofneumaudbehavioral plasticitythatallcwti braintocapewith&anging conaitionsin internaland-1 environlnmt. Ithasbeenprqosed that changes inthe synapticplasticityofcertain neuralne~rksunderlieimportantcognitivefunctionssuchaslearniragand~~(Lynch and Bavdry,1984). Evidenceis mlatingthatthereisa severeage-related deficitin him synapticstructureard functionthat~yberelatedtothelossofcognitive abilitiesfound in sane individuals with advancedage (Iandfield, 1983; Tielenet al., 1983). IJaklwer,theaMtanicalchangesfoundinthehippoc~s(changesin~ densities,lipofuscin~tion,thepresenceandaggregationofhypertrophiedastrocytes)arenattheonlychangesassociatedwithadvancedagenoristhe~~the onlyareainwhichsuchchangesoccur. abservedchangesincludedecreases-ofa--and B-adrenergic receptorsin the neocortex(Misraet al., 1980: Greenbernand Weiss. 1978). changesinne uronalnmrbranefluidityand subsequent;'availability" of nmnbrane&ept&s CinG.noet al., 1984),and a host of wgic changesin the basal gangliaand elsewhere (e.g.,Demarestet al., 1980; Govoniet al., 1977;McGeeret al., 1977). In pzopledeclinesinD2rece~rs (andS2serotoninreceptors)havedesonstratedusi1~~ positronemissiontaxqraphy (mg et al., 1984). AIlmxt every m ptative t?mlsmitw, in fact,haskeen shcwntofxhibitage-relatedchangesard,inaddition,reductionsof metabolicactivitieshave been demonstrated(e.g.,Ferriset al., 1983; Fosteret al., 1983). Since themslanocort ins have a wide range of physiologicactivitiesthat enhance adaptivecapabilities theymaybe a particulariqortance to age-relatedcocjnitive disorders. Afundammtalissue arises frcantheobservationthata specificmessagesite inthe rnelanocortin~leculemayinduceprofaundneurotraphiceffects,oneexampleofthisbe~ its beneficialrole in recovzyfrunperi@eralnervedamage. Inaddition,ACrH/MsH-like peptidesproducean enhancement of cerebraloxygen conswp?tionandglucoseutilization. Therefore,fllchneuropqtides may iqxove the adaptational abilities of the nervoussystesl andmaybe suited for clinical testing for the counteracting of age-relatedbrain pathologies. Inthepresentarticle,importantzasons for testingthe efficacyof the selanoco* inprovidingrelief fromage-relatedbrainabnorxalitieswillbereviewed. 2. TrophicEffectsof Mslw In additionto the elicitationof their specificphysiological responses,pituitary peptidehornoneslike ACD-IandMSH (Fig.l) exerttrophicinfluencesenhancingtben&abolic activityand the viabilityof their targetcells. Suchinfluencesincludeenhaxedblood flawthroughthe targetregionwithconseguentincreasedsupplyOf0xygenandnutrients. ted s~lationby these hormonesof target cell FuMxrnore, there is a wellnacrcnolecular synthesis(RNA/protein).Takentcgether,suchresponsesrepresenttrophic on targetcells. Cne exanpleof this influencesof the pituitarypeptidea influenceis illustratedby the nearly completeatrophyof the adrenalcortex in rats frun whichthepituitaryhasbeenextirpatedexperimantally. In line with the notionthat part of the brain and behavioraleffectsof the nval~ resultfrunpeptide actionsonneurons ard/orgliacells that are similarto those seen in paptide-target cells interactions in peripheral,non-neuraltissues (Gispen,1980),it iS notsurprisingthattheremwalofthepituitarycausesdr~ticreductionsinratbrain RNAandproteintUnover rates Gispen and 5&otman, 1973). subcutaneaus administration of ACIX, or fragmentsof it that do notaffectthe endocrineglands,tohypophysectcmized rats lead to marked overallincreasesin the synthesisof thesebrainmacxorrplecules (Ixmnand S&otnan, 1981). ,additi~,~~treatment~~~~~~~~~~~~~~ (Org 2766; Fig. 1) resultsin a highly localizedenhancanen hiplxxaqus, thalamus,and anteriorcingulatecortex O@Cullock et al., 1982). ‘I~E
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Fig. 1.
9
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2766
a=MSH
Primary structure of ACTH, a-MSH and Org 2766.
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biologicalsignificance ofneurotmphic influencesof themGmocortinsbecme especially apparentin studiesof the facilitation of the devel~t and maturationof the rat central nervoussystem. This is evidencedby increasedfetalbraingrmth andearliereye opening i.nneLlrop.?ptide-treated animals (Swaaband Martin,1981; Van der Helm and de Wied, 1976). Giventhese~~~cprapertiesofthemelanocortins, furtherinvestigationswere ne&edtodiscoverwhether these neu,?qzeptides could supportadaptim responsesof neural tissueafterdamagebyenhancingtheregenerationof fibersthatnormllyrepresenta portionoftherepairmechanisosthatoccurafter~~. 3. RecoveryfmPeripkralNerveDarrage Becausethe histologicaland functionaldeterioration found after crushingthe sciatic nerve of theratarewellkmm, thisprewationis useful for testingthe possible beneficialrole(s)that melanccortins my play in the nerve repairprocess. In fact, previousandpresentresearchof several groups have dccumenteda directeffectof ~lanocortinontheneural aspect of theneumnUscular~ system (TbrdaandWolf,1953; KrivoY,1970; Strandand snith, 1980). Strandand Snith (1980)were the first to reuort that kTH treatmentin rats f0ihhg nerve crush of the Sciaticmeme enhamed recovery of sensorimtor functionofthe affected link asmeasured in foot-flickand toe-spreading tests. Xl’Htrea~tresulted inanore rapidoutgrmthofregenerating axons, 1arge.r rotor endplates,and enhancedomummce of pretenniml branch& in the endplatearea Fkm.nd and smith,1980). Insubsequentstudiesitwasshawnthatneuropeptidetreatment selectivelyenhanmdthe formationof smallmotor units (Saint-&maet al., 1982). Using a pinch test, Vergheseet al. (1982)reportedthat neuropeptide treatmentof rats with a crush lesionin the sciaticnerve did not enhancethe regeneration of the fastergrcwing sensoryaxons. However,resultsobtainedby the pinch testpmcedure maynotberepresentativeofthepatternofgrawthof~sensory~~axons,~sthatsubserve thetypeof sensoryinfomationiqmtantfor that particulartest or be thebestestimaka of the averagerate of sensorynerve regeneration, overall. In a seriesof experimnts the r&auccortins facilitation of recowry ofsensortir functionsin the rat after sciaticnerve damge was confined (Bijlanaet al., 1981). Iktailedstmcture-activitystudiespointedto (1)extra-adrenal effectof the peptides,and cmponentrespon(2) amelarotrophic,ratherthan~~~~c,actionthatmaybethe sible for the enhancanentof regeneration(Bijlsnaet al., 1983c;Fig. 2). This conclusion anda-MSHarea&iveintk isderived,inpart,franthefactthatACIH/a-MSH analog,Org 2766 regenerative prccess,MMareasACIR/a-MSH is not?4he syntheticZCTH (Fig.2) has a nmber of centralnervous 4FJstm effectssimilarto thos&Zf ACTH althoughits melamtrcphi@&~ scme situationsit is 1000xmre activethan ACITi are rmch less than that of MSH itself (&aven and4&.o&d, 1973). However,intestsof neuralregeneration, its trqhic activityis egual to that of pIcIHq_lo. Inorderfor neuropeptidetreatmenttoberoaximdllyeffective,~treatrnent~tbegin imnediatelyaftfzthesurgery. Evidencehas!zeencbtamedtosuggestthatthereisa criticdlperiodin~chtheneuropeptide~~~tiseffedivethatbeginswiththecrush Iheactualtimeintervalpmbablyde~onthe ofthenerveandmaylast6to8days. particularnervethatis crushedand other factors (Edwardset al., 1984). Subeqwnt kistologicdlstudieshwefaurdthetreatmentwithrnelanocortinsresultinanincreasein then~ofnewlyfonwdneuritesattheareaofthecrush. FoTscmareaSan,the regenerationin the vehicledi~~softhenwritesaresmdllerthan~faundduring treatedcon-1 animals (Bijlsmaet al., 1983a,b). These observations may be related to of mall motor units (Sai.nt-@iea et al., 1982). aselective regeneration Insmmary,~datasuggestthattheneuropeptidetreatmentincreasesthe~~of neuritesfmnthe crushednervethattillbealrebothmyelinatedandunmyelinatedfibers not affected. (Bijlma et al., 1983a). The rates of grwkhof the newites is apparerrtly PublisheddatashcrwthatthereisMeffectoftheneurapeptideanthe~SOf~linaticm, itself. This excludesthe pcesibilitythat ths beneficialeffect of the lia~ingthe nemqepUdetreatm.ntis~cducedbyactiousontbeoligodendrog regeneratingmyelin.
Melanocortins, neural plasticity and aging
Reduction of recovery period
ACTH 4-10
6-M
Org
2766
PDLP
ACTH 1-16 u-MSH
Fig. 2. Melanocortins and return of peripheral nerve function after damage. Functional test, treatment schedule. and surgery can be found in Bijlsma et al. (1983c). Total recovery period 21 days. Peptides were given every other day, 10 pg/O.5 ml saline/subcutaneously. Qrg 2766 * ACTH4_g analog. PDLP - Phe-D-Lys-Phe (C-terminalpart of Org 2766).
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Inviewoftheevidehceofthe stimiiatinginfluence of malanocortins on the synthesisof proteinsin brain and spinalcord (IMnuand S&&man, 1981; Bijlsmaet al., 1984),it has beenarguedthattheenhancanentofremvery could be the result of inmmmad availability ofstructuralnmbraneamd cytoskeletdlproteinsthatarerequiredfartheformaticrmof the buddinggrowthcones as well (Bijlma et al., 1984). Detailedanalysisof the effect onthe synthesisof cytoskeletalproteinsliketubulin andactin,do mt suppxt %??%&%%a~& et al., 1985a). Hcmaver,thereareanmberofalternative~srrrs of neuropeptide actionsthatcmldhastenbehavioralrecmery afternervecrushthatnust beevaluatedin futureresearch. Cme attractivehypothesisbasedoncurrentlyavailabledata on the effectsof MSH in the peripheralnemous systemcmes fmn the work of E&au?& et al. (1984). They &served that a specificneurofilamant proteinwith a xtolecular weight of 150 kDa cross-reacts with an autise.xumtoa-MSH.Althovghthisantibodyreadsonlywiththeser-tyr~acidsinthe N-terminalMSH seguenceof neumfilamantprotein (Shawet al., 1985),antiseradimcted otberportions0ftheMSHpeptide intheregionoftheC-tenniMl@onappeartostaintD the filamantproteinaswell (Verhaagen etal., inpreparatim). secondly,Politissnd Spencer (1983)reportedthatahumralfactorderived frandegeneratingnervetissuearound the site of the lesionfacilitatesthe repairof the crushedsciaticnerve. Schlaepferard Has&r (1979)and Edwardset al. (1985b)shcwedthat mushing of the nerve led to a calcimactivatedbreakdcxmofthe 150 kDaprotein. Inaddition,ithasbeenshownthatthe cytosolicfractionof the degemerating,butnotthe controlrkarveitself, containedMSH-like activity,as determinedin a mslmxphore dispersionbioassay (lkbards et al., 1984). Therefore, it is possiblethatthedamage to aperipheralnerve couldtriggerlocalreleaseof malanotrophic factorsthatareessentialto therepairprccess. ThebeneficialeffectsOf treatnwt withmalaxcox+m ofratswith sciaticdamage,therefore, is thoughttoeflect aphamacologic au~~ti~ofanaturalphysiologicdlresponse tothedaIt?age, itself (Edwardsand Gispen,1985). 4. Hippoxqal Plasticity Ina seriesofexperinents,Landfieldaadhis associateshavetestedthehypothesisthat changesintheneural -endocrineinteracticmsmaybeof specific relevance tochangesin brain regionsthatcontaincytoplasmicaxdnuclearreceptorsfor the glucocorticoids such (Laudfield, et al., 1981). l?mnthisworkithasbeccn~possiblethatcertain~es as ~~tof~trocytesizearadn~as~llastheirdispersi0ninthehiFpolbrmver, inadultratsmaintained canpusarerelatedtocirculatingcorticosterone 1WdS. onhighdosesofcorticosteroids for 6 to7monthstherewas enhancedevidenceof glia reactivity~ccmparisontoage-matchedcontrolswithoutsuchtreatrnent.Conversely,in adrendLectaniz~ratsmaint&nedonalmdoseof corticos~ids, therewaslessglial 1twasarguedthat enhaxed levelsof Ac!rH pathologythanobsemed inthfZ!iXltdCtanimalS. inducedbythelawlevelofcorticosteroids~e~~~theusudLchangesfoundin thehippocmqmvtfthage. %echangesareUmughttobethecmseqmmof~ et al., 1986). intracellularCa levelsinducedby the glucocorticoids(Iandfield Iandfieldrrmmred the effectiveaess of chronicadministration of Org 277 to aging rats. The Crg 2766 is without periI_jeral effects. Hefaundthataf~9mnths0ftreatmmtwi~ ~2766f~oftheusudleffectsofaging~faunlwhenthebrains~~' animdls27 rmnths old. mepeptide-treated~shadanincreaseddensityof-adds Inaddition,hefa.mdthattheneurapeptide-tratedteds ~fewerreactiveastnxytes. displayedlatencyt.imssin a revSsallearningtaskthatweresimilartoyulngercontrols andlesslike the agenatchedcoborts (wield,1983). Themechanimbyw3‘Lichthese effectsof ttkaZQE+related mmqept&s occurs is largelyunlmmn. It is possiblethat a changedfluidityofSyMptoscmdlmfxbranesmyberespmsible, atleastinpert, for*_ alteredneUalactivities occmingwithinthehi~fol.lmingneuropeptide~tration (Hers~tz et al., 1982a;Hershkmits, 1983). v and relatedpe23tides mY increaseapparent lipid fluidityofbrain~~, inBtbesynapticPl_ et al., 1982b:Van Dorrgen rmrbranesde.rimadfranthehipjqBFus of older rats (Ilershkawitz tidditicmal invivodata on Ixmmnal~ane~bearingoa et al., 1983). clearly, themechanismsthrougfiwhich~treatrnentInay~~~lossesinneuroplasticityof agiragareneeded~~~representaninportantareaforfutureresearch.
Melanocortins, neural plasticity and aging
421
Presently, several reports have been plblished that suggest that, with peripheralnerve damage,the effects of dmiqe in the cfmtral nervous systm may bs reducedbyrnM with melamcortins and related peptide fragments. Isaacsonand Poplawsky(1983,1985)used thedisappearanceofhypergnotiondlity~byseptdlarealesicnsasanindexof and m 2766, given subcutanfurlctional ?xcovwyfranhraindirmage.Ihepeptides~ eously for four consecutivedaysbeginningimnediatelyaf~"surgery,resultedina~ler than usual lesic4Gkkwd ixrease in ewtionality scores. The Orq 2766 treatxentalso facilitated theretuwtonormalvalues over subsequent days after surgery. This is shown . * onerxkionalitywasfoukionlyantkfirst I%mever the effect Rzduoed~onality :sz$ &&&as also the wasnotfoundon subsequenttestdays. Hcwzver, that the AcrH fragmentwas not given for a sufficientnurkerofdays, since Gispen&his caworkershave fcuryd that a seriesof treatmzntslastingat least 6, and preferably8, days after nerve crushxnxt be given in order to find facilitation of recovky (Edwa& et al., 1984). weeks after the daily tests for enxkionalitvcriven bv Isaacsonand Poplawskv(1983,1985),the animalsvere tkinedonthe two-way&ve av&ance task. lhe-typicalincr&seinavoidanceperforlMnceseeninanimalswithseptallesionswas obserwAi.n~lesionedaninKis butonlytheGrg2766 treatmsntreducedthenutkerof Fated F by Org 2766 Or -$@I& of the septallesion_ mter-trldlresponsesthatare
Pdditio~dataontheeffectsofmel~ontherecweryfrcmbrain~~~ franstudies onthe functionalrecoveryafter lesionsof the parafascicular nucleusin the rat (Nyakaset al., 1985). Int.hesestw3ies,rats~esubjectedtoadailytreatwntof either c(-MsH, Org 2766, or salinebeginningthe third day after suqwy~lastingfor~ After caqletionofthechronic neutqeptidetreakrent,thelesionedanimals weeks. acquiredareversdlle~taskinaTmazewithf~errorsthandidthesdline_treated earningdeficit,a-MSHsem& controls. Basedondose-de~tre&ctionoftherewrsal1 to be mre potent than Org 2766. This conclusionhasbeensqqxtedbythe findingthat a-MSH, but not Org 2766 (in a relativelyhigh dose), slightlyaaneliorated the abnonral. graspingrespcnseinducedby the parafascicularlesionbythe endof the treatment period. SinceacutetreatmentwithOrg2766ora-MsHdoeslaotinfluencerarersdLperfornranceinthe lesionedanimals,itwas con&.&d that the beneficialeffectoftheneurqeptide treatment couldbe explainedin terns of facilitationofrecoveq ofcognitivefunctionsinratswith bilaterallesionsin nucleuspaxafascicularis.Whetherthe facilitationoffunctionby mel~afteroentralnervous systgndamagedependsonan enhancarwt of cellular responsesirnrolvedintherepairmxhanisns,asfoundintheperipherdlsystem,remainsto bedew. Nevertheless,thesedatamayserve asa fi_rstikLicationthatmelaxx&ins have abeneficialroleas trophicfactorsin the centralnervoussystanafterdamage. Otherexperimentsindicatedalessenedeffedof~a~~intheperformanceofa tw-way a&&e avoidancetask by administration of ACI'H(Bushet-al.,1973) and a reduction by Org 2766 of presur& attentionaland "wrking mznxxy"deficitsprodwed by hippocan@ lesions (Hanniganand Isaacson,1985). 6. EehavioralPlasticity Insightinthe roleofmelanccortinsinadaptiveb&aviors originatesfrunstudiesbya varietyof researchgroups~loyingxtkmydifferentbshavioralparadigms(forinstance: active anl passiveavoZlancebehavior,zwardedbehavior,discrixninationtasks,reversal behavior,sexualandsocialbehaviors,etc.;seedeWiedandJolles, Tlw . Prior totheprecise localizationofpepti~gic neuronsomtaining w nEkuwcortins (Kriegeretal., 1980),behavioralstudiesindicatedthatthebrainhadtibe regardedasatarqetforpi.Mkary-peptidehcrnxxw andtheirfraqEnts.deWiedadwmced theconceptthat neuropeptidescculdbeiqxztantmxlulatorsofneuronalfunctions&that specificproteolysis of pro-psptideswould~atehighly selectiveanlnwepotentpeptide ccolfigurationsthatmightbeinvolvedinlocdlandsubtleregula~ofbrainhaneostasis
422
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16 I5 14 I3 12 II ItI 9 6 7 6 5 4 3 2 I
DAYS AFTER
SURGERY
3. The mean emotionality scores of animals with septal lesions treated with saline (triangles),animals treated with Org 2766 (open circles), and control animals (filled circles) over repeated tests, starting thethirdday after surgery. From Isaacson and Poplawsky (1983).
Melanocortins,
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(de Wied, 1969, 1978). With respectto the mltiplicity of effectsof m&mocortins on adaptivebehavior,EQhus and de Wied (1980)fomlated the unifyirqmechanismthat in part is basedonneurophysiologicalfindingsthatthesepeptides increasedthearousal state in r&brain-ltiic structuresand increasedvi.gilance (seealso, de Wied and Jolles,1982). They fommlatedthehypothesis that ACTH andrelatedpeptides,bytemporarilyincreasing the stateof arousalincertainltiic systemaridlimbicsystem-relatedstructures of the brain,enhancedthem%ivationalvalue of envirormmtalstirmli. Insuch awaythepeptides may increasethe probabilityof generatingstimlus-specificresponses.
Based on thevastamuntof animaldata sugyestingthatmalanocortinsfacilitatebehavioral adaptationby improvingmotivationand attention,a varietyof studieshave been performedinvestigating the behavioralprofileof these peptidesin human volunteersand patients. Althoughour presentknmledge onthe effectiveness ofm&mccortins inhuman behavioralperfonmnce is far frun omplete, a picturemerges that shcws a surprisingly gocd coherencewithwhatiskrmmas thesepeptidesin animalstudies. Thus,despitethe relativelysmall number of studies,fraqents of ACI'Hand MSH seem to affecthuman EM; activitywhen recordedduring stkmlation or information processing(Rmncomiec, 1981). Interestingly, Gaillard (1981)ascribesthe irqrovemsntinperformanceofvollluteers during amnotonous serialtestsituationto apeptide effectcmtask-orientedmScivationor sustainedattention. Hence,thereisaresemblanceintheinterpretationofboththeanimal ardhmrandata. Althoughthe effectsof melanccortins on hman behaviorare mdest, they myhave sans advantageover presentlyavailablepsycho-stimulants inthattheyhave fewer adversiveside effects. In view of the hman behavioralprofileard the neumtmphicpropertiesofmalanocortins, it is expectedthatsuchpeptidesrrayexertbermeficialeffects onnrantalperfomanceof the agedhmanbeing. Recently,a nh of excellent reviewshave addressedtherole of ACTHlike peptidesin elderlyanimalsand paople (Pigacheand tigter,1981; Branconnier, 1981). Bnployinga serialreactiontine test in mildly senilesubjects,Branconnieret al. (1979) fourdthattreatmntwithACEi &~~~~ression of increasedreactiontimes resultingfmn continuousperf Furthemmre, the subjectsdisplayed reduceddepressionand confusion. This latteraspectof the subchronicpeptidetreatnwt is of interestas variousauthorshave reportedthat chronictreatmentof elderlyand/or nuderatedemsntedhuman beingswith Grg 2766 reducedanxietyand depressionand enkmced feelingsof cunpatenceand made the patientssore sociable (deWied and Jolles,1982). Again there seems a parallelwith the animal data, as it has been reportedpreviouslythat kxxeases the nmber of socialcontactsamong rats (Beckwith et al., 1977;File, -41979;&?esinkmd Van F&e, 1983; Spruijt,1985). 7. Conclusions In view of the well-dccmentedeffects ofmalanocortinsonneuralandbehavioral plasticityinanimals, it is appropriatetoconsidertheirpotentialityinhumandiseasesrelated to loss of brain plasticityand which are manifestwith inueasingage (GispenanddeWied, 1984). At presentlittleinformationis availableon possibleamlioratingeffectsof lsGmoco~treatlsantofpatientswithdiseases suchasseniledemntiaoftheAlshei.mr's type. The data so far seem to indicateonly small, if any, inprovenmtsofthediseased subjectsaftertreatmsntwithmsl.anoco&ns. lhemajorprablsrnwithclinicaltestingof thesenrm_~cpeptidesderivedfrrrnACTHandMSHisdesigningaproper~~tschedule (route,dose,period,etc.)andthechoiceof*prqergroupofpatients. Especiallywith reqect of the modest,but specific,mdulatory effectof melanocortins on brain and behavior,it may be that beneficialeffectsmight be producedonly if tipaptides aregiven dmingtheveryearlyphasesofthebrainpatiology. Ashasbeenstressedbynearlyall , early and specificdiagnoses con~aq scientistsin the field of age-relateddiseases are prerequisites for furtheringaurinsightin thediseaseprccess. I+rthermore, there is agrawingbodyofLiteraturedarrmstratingadiversi~withintheAlzheuner'sdisease cateqxy,perhaps thenrxtdevastatingbeing thatwithauearlyonset (Mayeuxetal.,1985). Tbeseckervations furtherunderscoretheurgentneed for as earlyadiagnosis as possible fortheage-relateddfmantias.
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BECKWIT& B.E., SANDMAW,C.A., HCE%ZAU, D. and KASTIN,A.J. (1977) Influenceof neoMtal injectionsof a-MSB onlearning, -r-y and attentionin rats. Physiol.Behav.18: 63-71. BIJUNA, W.A., m, F.G.I.,XHOIMAW, P. and GISPEN,W.H. (1981) Effectsof=rtirecoveqofsensorirrntorfunctionintherat: structur e-activity . ELu. J. Phannxol. 76: 73-79. =ti(-)on BIJISMA,W.A., VAW ASSEGT,E., VEIdXAW,H., JFSJNEXENS, F.G.I.,SCHCYINAN, P. and GISPEW,W.H. (1983a) Ultrastructural study of the effectof _(4-10) on nerve regeneration: axons beoxnelargerinnL&erandsMllerindiamster. &ta Neuropathol.(Berl.)2: 24-30. BIJIZMA,W.A., -S, F.G.I.,w, P. and GISPEW,W.H. (1983b) Stinulation by AClB(4-10)of nerve fiber regenerationfollowingsciaticnerve crush. Muscle & Nerve 6: 104-112. BI-%SMA,W-A., SUXYRQW, P., JENNE@NS, F.G.I.,GISPEN,W.H. and DE WIED, D. (1983c) me enhancedrecoveq of sensorimotorfunctionin rats is relatedto the ~lanotropic moiety ofACI'B/MSHnewqx@ides. Eur.J.Pharmaco1. 92: 231-236. BIJU%?L,W.A., w, F.G.I.,SCHOTMAN,P. &GISPEN, W.H. (1984) Neurotropicfactors and regeneration in the peripheralnervoussys+xn. Psy&oendccrinolcgy 2: 199-215. BOHUS,B. and DE WIED, D. (1980) Pituitary-adrenal systemho?zxxxasandadaptivebehaviour. m:~~,ornparativeandClinical~inologyofthePdreMlOartex,I.olester Jones and W.H. Henderson(eds),Vol. 3, pp. 265-347. IIcademic Press,Iondon. BRANCONMER, R.J. (1981) The human behavioralphannaco logyofthecclmrm core heptapeptides. P-1. 'Iher.14: 161-175. B, R.J., m, J.O. and CXUXX, G. (1979) ACIH(4-10)in the arsalioration of neuropsychologicalsymptcmatologyassociatedwithsenilearganisbrains~. Psy&ophan~cology 61: 161-165. BUSB, D.F., IOVELY,R.H. and PAG?N& R.R. (1973) Injectionof ACTB inducesrecoveryfran shuttle-boxavoidancedeficitsin rats with amygdaloidlesions. J. canp. physiol. Psychol.83: 168-172. G. (1984) c. and m-1, CIMIWO,M.N, G., AIGERI,S., CDRATLA,G., PEZZCILI, Age-relatednrodificationof~gicand 8-adrenxgicreceptorsystenurestorationto nazTpalac&ivitybymxzifyingmsnbrane fluiditywithS-a&nosyln&hionine. Life Sci. 34: 2029-2039. of mic D-T, K.T., RIBXE, G.D. and MXKBX, K.E. (1980) Characteristics neuronsin the aged male rat. Weuroe&xxinol. 31: 222-227. DE WIED, D. (1969) Effectsof peptidehornrxeson%havior. m:Frontiers inWeuroendocrinology, W.F. Among a~%?L. Martini (eds), pp. %'-140. Oxford t_himSitY Press, New York. DE WIED, D. (1978) Psychopathology as a neurqeptidedysfunction. Dev. Weurosci.~: 113-122. DEWIz),D. andJcxr.ES,J. (1982) Weurope~de;fsved f~proopianelanocortin: . Physiol.Rev. 62: 976-1059. behavioral,physiologicalti~ DUNW, A.J. and scHD?MAN,P. (1981) Effectsof ACIB and relatedpeptideson oerebralPNA and proteinsynthesis. Phaumcol. T&r. 12: 353-372. F.G.I.arxd EUVAPDS,P.M., VAW DER ZEE, C.E.E.M.,VmWikiN, J., SCHWE@N, P., B, GISPEN,W.H. (1984) Evidencethat the neurotrophic actionsof a-MSRmay derive fran its abilitytomirr& actionsof apeptide formedinmatingnsrve stunps. J.Neurolog. Sci. 64: 333-340. F.G.I.and GISPEW, nTP.M., VERHAPGEN,J., SPIERINGS,T., w, P., -S, W.H. (1985a) The effectof ACm(4-10) on proteinsynthesis,actin ard tubulinduring regeneratian.BrainRas.Bull., inpress. F.G.I. and J., -, P., -S, IXWARDS,P.M., VAN DES ZEE, C.E.E.M., -, GIsPm, W.H. (1985b) MSB and its analoguesin peripherdlnerve regeneration.Dutch Fed. Proc., 81. ELWARDS,P.M. am3 GISPIN, W.H. (1985) lvktlanwartin &‘SptideS ard MIIpdl @StiCityIn: senilea311321ti
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Grg i766.anda-MSH.onreversallearningof rats with bilateralmlesions of the parafasciculararea. BminRss.Bull.,inpress.
Neuro-Psychopharmncol.
Printed
in Great
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6 Biol. Psychiot. All rights
1986.
Vol. 10. pp. 415426 Copyright
reserved.
MELANOCORTINS,
WILLeM
NEURAL PLASTICITY
0
0276-5646166 1986 Pergamon
$0.00 + .50 Journals Ltd.
AND AGING
HENDRIKGISPEN,ROBEFCC L. ISA?CSON,l,BERRYM. SPRUIJT andDAVIDDEWIED
Divisionof ~lecular Neurobiology, RudolfMagnus Institutefor Pharmcolcgy and Instituteof Mxhcular Biology,StateUniversityof U-&e&t Padualaan,CHUtrecht TheNetherlands %e partnmk of Psychologyand Center for NwrokehavioralSciences UniversityCenterat Binghamton Binghamton,NY U.S.A. (Finalform, February1986)
AbStiaCt
1. 2. 3. 4. 5. 6. 7.
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Intrcduction TrophicEffectsofhklamcortins RecoveryfranPeripheral Nerve Damage HippocampalPlasticity RecoveryfrcmBrainDamage BehavioralPlasticity Conclusions ~ferences
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Gispen,Willem Hendrik,F&ert L. Isaacson,Berry M. Spmijt and David de Wied: Mslanocortins, neuralplasticityand aging. Prog. Nemo-Psychophamacol.& Biol. Psychiat.,1986,g (3-5):415-426. 1. PeptidesderivedfranACHTand a-MSHarekncwntoexerktrophic influenceson peripheralandcentralnemous structures. :. we -related.braindiseasesmayinpartke relatedtoloss ofneuralplasticity. Melanocortins hqzove adaptionalabilitiesofthe nervoussystem. 4: Chronictreatmntwithmlanccortinsmycoun~act age-relatedbrainpathology. neural Keywords: ACIH, a-MSH,behavioralplasticity,brain aging,nerve regeneration, plasticity,neurotmphic effects. Abbreviations: pdrenocorticotropic honmm (ACTH),Calcim (Ca2+),Dzpmine receptor, type 2 (D2),ThousandDalton~aswe (kDa),mlamcyk-stirrailating w(s) (MSJ-0 rikonucleicacid (RNA),a-ml amcyte-stimulatinghorrmne(a-MSH),Serim(ser),Serotonin receptar, type 2 WI, Tyrosine kYd
415
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1.
et al.
Induction
Inthepast25 yeam or so, trmmdominsighthasbsengaimdwithregardtothe functionsoftheIIelanccortins system activities.Variw disciplines w-Jwm3-u on Ilervms within~neuroscienceshaveindicatedaroleofthesepeptidesinbrainandbehaviar,and these investigations haveledtoaniqxessivenmberof functional, adaptivethat seem to be nodulatedby the malanocortins(DeWied and Jolles 1982). Ihe &z mechanisms inbrainandbehavior areoftendescribedintmmsofneumaudbehavioral plasticitythatallcwti braintocapewith&anging conaitionsin internaland-1 environlnmt. Ithasbeenprqosed that changes inthe synapticplasticityofcertain neuralne~rksunderlieimportantcognitivefunctionssuchaslearniragand~~(Lynch and Bavdry,1984). Evidenceis mlatingthatthereisa severeage-related deficitin him synapticstructureard functionthat~yberelatedtothelossofcognitive abilitiesfound in sane individuals with advancedage (Iandfield, 1983; Tielenet al., 1983). IJaklwer,theaMtanicalchangesfoundinthehippoc~s(changesin~ densities,lipofuscin~tion,thepresenceandaggregationofhypertrophiedastrocytes)arenattheonlychangesassociatedwithadvancedagenoristhe~~the onlyareainwhichsuchchangesoccur. abservedchangesincludedecreases-ofa--and B-adrenergic receptorsin the neocortex(Misraet al., 1980: Greenbernand Weiss. 1978). changesinne uronalnmrbranefluidityand subsequent;'availability" of nmnbrane&ept&s CinG.noet al., 1984),and a host of wgic changesin the basal gangliaand elsewhere (e.g.,Demarestet al., 1980; Govoniet al., 1977;McGeeret al., 1977). In pzopledeclinesinD2rece~rs (andS2serotoninreceptors)havedesonstratedusi1~~ positronemissiontaxqraphy (mg et al., 1984). AIlmxt every m ptative t?mlsmitw, in fact,haskeen shcwntofxhibitage-relatedchangesard,inaddition,reductionsof metabolicactivitieshave been demonstrated(e.g.,Ferriset al., 1983; Fosteret al., 1983). Since themslanocort ins have a wide range of physiologicactivitiesthat enhance adaptivecapabilities theymaybe a particulariqortance to age-relatedcocjnitive disorders. Afundammtalissue arises frcantheobservationthata specificmessagesite inthe rnelanocortin~leculemayinduceprofaundneurotraphiceffects,oneexampleofthisbe~ its beneficialrole in recovzyfrunperi@eralnervedamage. Inaddition,ACrH/MsH-like peptidesproducean enhancement of cerebraloxygen conswp?tionandglucoseutilization. Therefore,fllchneuropqtides may iqxove the adaptational abilities of the nervoussystesl andmaybe suited for clinical testing for the counteracting of age-relatedbrain pathologies. Inthepresentarticle,importantzasons for testingthe efficacyof the selanoco* inprovidingrelief fromage-relatedbrainabnorxalitieswillbereviewed. 2. TrophicEffectsof Mslw In additionto the elicitationof their specificphysiological responses,pituitary peptidehornoneslike ACD-IandMSH (Fig.l) exerttrophicinfluencesenhancingtben&abolic activityand the viabilityof their targetcells. Suchinfluencesincludeenhaxedblood flawthroughthe targetregionwithconseguentincreasedsupplyOf0xygenandnutrients. ted s~lationby these hormonesof target cell FuMxrnore, there is a wellnacrcnolecular synthesis(RNA/protein).Takentcgether,suchresponsesrepresenttrophic on targetcells. Cne exanpleof this influencesof the pituitarypeptidea influenceis illustratedby the nearly completeatrophyof the adrenalcortex in rats frun whichthepituitaryhasbeenextirpatedexperimantally. In line with the notionthat part of the brain and behavioraleffectsof the nval~ resultfrunpeptide actionsonneurons ard/orgliacells that are similarto those seen in paptide-target cells interactions in peripheral,non-neuraltissues (Gispen,1980),it iS notsurprisingthattheremwalofthepituitarycausesdr~ticreductionsinratbrain RNAandproteintUnover rates Gispen and 5&otman, 1973). subcutaneaus administration of ACIX, or fragmentsof it that do notaffectthe endocrineglands,tohypophysectcmized rats lead to marked overallincreasesin the synthesisof thesebrainmacxorrplecules (Ixmnand S&otnan, 1981). ,additi~,~~treatment~~~~~~~~~~~~~~ (Org 2766; Fig. 1) resultsin a highly localizedenhancanen hiplxxaqus, thalamus,and anteriorcingulatecortex O@Cullock et al., 1982). ‘I~E
12
345676
456769
Fig. 1.
9
11
12
13
2766
a=MSH
Primary structure of ACTH, a-MSH and Org 2766.
10
@g
biologicalsignificance ofneurotmphic influencesof themGmocortinsbecme especially apparentin studiesof the facilitation of the devel~t and maturationof the rat central nervoussystem. This is evidencedby increasedfetalbraingrmth andearliereye opening i.nneLlrop.?ptide-treated animals (Swaaband Martin,1981; Van der Helm and de Wied, 1976). Giventhese~~~cprapertiesofthemelanocortins, furtherinvestigationswere ne&edtodiscoverwhether these neu,?qzeptides could supportadaptim responsesof neural tissueafterdamagebyenhancingtheregenerationof fibersthatnormllyrepresenta portionoftherepairmechanisosthatoccurafter~~. 3. RecoveryfmPeripkralNerveDarrage Becausethe histologicaland functionaldeterioration found after crushingthe sciatic nerve of theratarewellkmm, thisprewationis useful for testingthe possible beneficialrole(s)that melanccortins my play in the nerve repairprocess. In fact, previousandpresentresearchof several groups have dccumenteda directeffectof ~lanocortinontheneural aspect of theneumnUscular~ system (TbrdaandWolf,1953; KrivoY,1970; Strandand snith, 1980). Strandand Snith (1980)were the first to reuort that kTH treatmentin rats f0ihhg nerve crush of the Sciaticmeme enhamed recovery of sensorimtor functionofthe affected link asmeasured in foot-flickand toe-spreading tests. Xl’Htrea~tresulted inanore rapidoutgrmthofregenerating axons, 1arge.r rotor endplates,and enhancedomummce of pretenniml branch& in the endplatearea Fkm.nd and smith,1980). Insubsequentstudiesitwasshawnthatneuropeptidetreatment selectivelyenhanmdthe formationof smallmotor units (Saint-&maet al., 1982). Using a pinch test, Vergheseet al. (1982)reportedthat neuropeptide treatmentof rats with a crush lesionin the sciaticnerve did not enhancethe regeneration of the fastergrcwing sensoryaxons. However,resultsobtainedby the pinch testpmcedure maynotberepresentativeofthepatternofgrawthof~sensory~~axons,~sthatsubserve thetypeof sensoryinfomationiqmtantfor that particulartest or be thebestestimaka of the averagerate of sensorynerve regeneration, overall. In a seriesof experimnts the r&auccortins facilitation of recowry ofsensortir functionsin the rat after sciaticnerve damge was confined (Bijlanaet al., 1981). Iktailedstmcture-activitystudiespointedto (1)extra-adrenal effectof the peptides,and cmponentrespon(2) amelarotrophic,ratherthan~~~~c,actionthatmaybethe sible for the enhancanentof regeneration(Bijlsnaet al., 1983c;Fig. 2). This conclusion anda-MSHarea&iveintk isderived,inpart,franthefactthatACIH/a-MSH analog,Org 2766 regenerative prccess,MMareasACIR/a-MSH is not?4he syntheticZCTH (Fig.2) has a nmber of centralnervous 4FJstm effectssimilarto thos&Zf ACTH althoughits melamtrcphi@&~ scme situationsit is 1000xmre activethan ACITi are rmch less than that of MSH itself (&aven and4&.o&d, 1973). However,intestsof neuralregeneration, its trqhic activityis egual to that of pIcIHq_lo. Inorderfor neuropeptidetreatmenttoberoaximdllyeffective,~treatrnent~tbegin imnediatelyaftfzthesurgery. Evidencehas!zeencbtamedtosuggestthatthereisa criticdlperiodin~chtheneuropeptide~~~tiseffedivethatbeginswiththecrush Iheactualtimeintervalpmbablyde~onthe ofthenerveandmaylast6to8days. particularnervethatis crushedand other factors (Edwardset al., 1984). Subeqwnt kistologicdlstudieshwefaurdthetreatmentwithrnelanocortinsresultinanincreasein then~ofnewlyfonwdneuritesattheareaofthecrush. FoTscmareaSan,the regenerationin the vehicledi~~softhenwritesaresmdllerthan~faundduring treatedcon-1 animals (Bijlsmaet al., 1983a,b). These observations may be related to of mall motor units (Sai.nt-@iea et al., 1982). aselective regeneration Insmmary,~datasuggestthattheneuropeptidetreatmentincreasesthe~~of neuritesfmnthe crushednervethattillbealrebothmyelinatedandunmyelinatedfibers not affected. (Bijlma et al., 1983a). The rates of grwkhof the newites is apparerrtly PublisheddatashcrwthatthereisMeffectoftheneurapeptideanthe~SOf~linaticm, itself. This excludesthe pcesibilitythat ths beneficialeffect of the lia~ingthe nemqepUdetreatm.ntis~cducedbyactiousontbeoligodendrog regeneratingmyelin.
Melanocortins, neural plasticity and aging
Reduction of recovery period
ACTH 4-10
6-M
Org
2766
PDLP
ACTH 1-16 u-MSH
Fig. 2. Melanocortins and return of peripheral nerve function after damage. Functional test, treatment schedule. and surgery can be found in Bijlsma et al. (1983c). Total recovery period 21 days. Peptides were given every other day, 10 pg/O.5 ml saline/subcutaneously. Qrg 2766 * ACTH4_g analog. PDLP - Phe-D-Lys-Phe (C-terminalpart of Org 2766).
419
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W. H.Gispen etal.
Inviewoftheevidehceofthe stimiiatinginfluence of malanocortins on the synthesisof proteinsin brain and spinalcord (IMnuand S&&man, 1981; Bijlsmaet al., 1984),it has beenarguedthattheenhancanentofremvery could be the result of inmmmad availability ofstructuralnmbraneamd cytoskeletdlproteinsthatarerequiredfartheformaticrmof the buddinggrowthcones as well (Bijlma et al., 1984). Detailedanalysisof the effect onthe synthesisof cytoskeletalproteinsliketubulin andactin,do mt suppxt %??%&%%a~& et al., 1985a). Hcmaver,thereareanmberofalternative~srrrs of neuropeptide actionsthatcmldhastenbehavioralrecmery afternervecrushthatnust beevaluatedin futureresearch. Cme attractivehypothesisbasedoncurrentlyavailabledata on the effectsof MSH in the peripheralnemous systemcmes fmn the work of E&au?& et al. (1984). They &served that a specificneurofilamant proteinwith a xtolecular weight of 150 kDa cross-reacts with an autise.xumtoa-MSH.Althovghthisantibodyreadsonlywiththeser-tyr~acidsinthe N-terminalMSH seguenceof neumfilamantprotein (Shawet al., 1985),antiseradimcted otberportions0ftheMSHpeptide intheregionoftheC-tenniMl@onappeartostaintD the filamantproteinaswell (Verhaagen etal., inpreparatim). secondly,Politissnd Spencer (1983)reportedthatahumralfactorderived frandegeneratingnervetissuearound the site of the lesionfacilitatesthe repairof the crushedsciaticnerve. Schlaepferard Has&r (1979)and Edwardset al. (1985b)shcwedthat mushing of the nerve led to a calcimactivatedbreakdcxmofthe 150 kDaprotein. Inaddition,ithasbeenshownthatthe cytosolicfractionof the degemerating,butnotthe controlrkarveitself, containedMSH-like activity,as determinedin a mslmxphore dispersionbioassay (lkbards et al., 1984). Therefore, it is possiblethatthedamage to aperipheralnerve couldtriggerlocalreleaseof malanotrophic factorsthatareessentialto therepairprccess. ThebeneficialeffectsOf treatnwt withmalaxcox+m ofratswith sciaticdamage,therefore, is thoughttoeflect aphamacologic au~~ti~ofanaturalphysiologicdlresponse tothedaIt?age, itself (Edwardsand Gispen,1985). 4. Hippoxqal Plasticity Ina seriesofexperinents,Landfieldaadhis associateshavetestedthehypothesisthat changesintheneural -endocrineinteracticmsmaybeof specific relevance tochangesin brain regionsthatcontaincytoplasmicaxdnuclearreceptorsfor the glucocorticoids such (Laudfield, et al., 1981). l?mnthisworkithasbeccn~possiblethatcertain~es as ~~tof~trocytesizearadn~as~llastheirdispersi0ninthehiFpolbrmver, inadultratsmaintained canpusarerelatedtocirculatingcorticosterone 1WdS. onhighdosesofcorticosteroids for 6 to7monthstherewas enhancedevidenceof glia reactivity~ccmparisontoage-matchedcontrolswithoutsuchtreatrnent.Conversely,in adrendLectaniz~ratsmaint&nedonalmdoseof corticos~ids, therewaslessglial 1twasarguedthat enhaxed levelsof Ac!rH pathologythanobsemed inthfZ!iXltdCtanimalS. inducedbythelawlevelofcorticosteroids~e~~~theusudLchangesfoundin thehippocmqmvtfthage. %echangesareUmughttobethecmseqmmof~ et al., 1986). intracellularCa levelsinducedby the glucocorticoids(Iandfield Iandfieldrrmmred the effectiveaess of chronicadministration of Org 277 to aging rats. The Crg 2766 is without periI_jeral effects. Hefaundthataf~9mnths0ftreatmmtwi~ ~2766f~oftheusudleffectsofaging~faunlwhenthebrains~~' animdls27 rmnths old. mepeptide-treated~shadanincreaseddensityof-adds Inaddition,hefa.mdthattheneurapeptide-tratedteds ~fewerreactiveastnxytes. displayedlatencyt.imssin a revSsallearningtaskthatweresimilartoyulngercontrols andlesslike the agenatchedcoborts (wield,1983). Themechanimbyw3‘Lichthese effectsof ttkaZQE+related mmqept&s occurs is largelyunlmmn. It is possiblethat a changedfluidityofSyMptoscmdlmfxbranesmyberespmsible, atleastinpert, for*_ alteredneUalactivities occmingwithinthehi~fol.lmingneuropeptide~tration (Hers~tz et al., 1982a;Hershkmits, 1983). v and relatedpe23tides mY increaseapparent lipid fluidityofbrain~~, inBtbesynapticPl_ et al., 1982b:Van Dorrgen rmrbranesde.rimadfranthehipjqBFus of older rats (Ilershkawitz tidditicmal invivodata on Ixmmnal~ane~bearingoa et al., 1983). clearly, themechanismsthrougfiwhich~treatrnentInay~~~lossesinneuroplasticityof agiragareneeded~~~representaninportantareaforfutureresearch.
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Presently, several reports have been plblished that suggest that, with peripheralnerve damage,the effects of dmiqe in the cfmtral nervous systm may bs reducedbyrnM with melamcortins and related peptide fragments. Isaacsonand Poplawsky(1983,1985)used thedisappearanceofhypergnotiondlity~byseptdlarealesicnsasanindexof and m 2766, given subcutanfurlctional ?xcovwyfranhraindirmage.Ihepeptides~ eously for four consecutivedaysbeginningimnediatelyaf~"surgery,resultedina~ler than usual lesic4Gkkwd ixrease in ewtionality scores. The Orq 2766 treatxentalso facilitated theretuwtonormalvalues over subsequent days after surgery. This is shown . * onerxkionalitywasfoukionlyantkfirst I%mever the effect Rzduoed~onality :sz$ &&&as also the wasnotfoundon subsequenttestdays. Hcwzver, that the AcrH fragmentwas not given for a sufficientnurkerofdays, since Gispen&his caworkershave fcuryd that a seriesof treatmzntslastingat least 6, and preferably8, days after nerve crushxnxt be given in order to find facilitation of recovky (Edwa& et al., 1984). weeks after the daily tests for enxkionalitvcriven bv Isaacsonand Poplawskv(1983,1985),the animalsvere tkinedonthe two-way&ve av&ance task. lhe-typicalincr&seinavoidanceperforlMnceseeninanimalswithseptallesionswas obserwAi.n~lesionedaninKis butonlytheGrg2766 treatmsntreducedthenutkerof Fated F by Org 2766 Or -$@I& of the septallesion_ mter-trldlresponsesthatare
Pdditio~dataontheeffectsofmel~ontherecweryfrcmbrain~~~ franstudies onthe functionalrecoveryafter lesionsof the parafascicular nucleusin the rat (Nyakaset al., 1985). Int.hesestw3ies,rats~esubjectedtoadailytreatwntof either c(-MsH, Org 2766, or salinebeginningthe third day after suqwy~lastingfor~ After caqletionofthechronic neutqeptidetreakrent,thelesionedanimals weeks. acquiredareversdlle~taskinaTmazewithf~errorsthandidthesdline_treated earningdeficit,a-MSHsem& controls. Basedondose-de~tre&ctionoftherewrsal1 to be mre potent than Org 2766. This conclusionhasbeensqqxtedbythe findingthat a-MSH, but not Org 2766 (in a relativelyhigh dose), slightlyaaneliorated the abnonral. graspingrespcnseinducedby the parafascicularlesionbythe endof the treatment period. SinceacutetreatmentwithOrg2766ora-MsHdoeslaotinfluencerarersdLperfornranceinthe lesionedanimals,itwas con&.&d that the beneficialeffectoftheneurqeptide treatment couldbe explainedin terns of facilitationofrecoveq ofcognitivefunctionsinratswith bilaterallesionsin nucleuspaxafascicularis.Whetherthe facilitationoffunctionby mel~afteroentralnervous systgndamagedependsonan enhancarwt of cellular responsesirnrolvedintherepairmxhanisns,asfoundintheperipherdlsystem,remainsto bedew. Nevertheless,thesedatamayserve asa fi_rstikLicationthatmelaxx&ins have abeneficialroleas trophicfactorsin the centralnervoussystanafterdamage. Otherexperimentsindicatedalessenedeffedof~a~~intheperformanceofa tw-way a&&e avoidancetask by administration of ACI'H(Bushet-al.,1973) and a reduction by Org 2766 of presur& attentionaland "wrking mznxxy"deficitsprodwed by hippocan@ lesions (Hanniganand Isaacson,1985). 6. EehavioralPlasticity Insightinthe roleofmelanccortinsinadaptiveb&aviors originatesfrunstudiesbya varietyof researchgroups~loyingxtkmydifferentbshavioralparadigms(forinstance: active anl passiveavoZlancebehavior,zwardedbehavior,discrixninationtasks,reversal behavior,sexualandsocialbehaviors,etc.;seedeWiedandJolles, Tlw . Prior totheprecise localizationofpepti~gic neuronsomtaining w nEkuwcortins (Kriegeretal., 1980),behavioralstudiesindicatedthatthebrainhadtibe regardedasatarqetforpi.Mkary-peptidehcrnxxw andtheirfraqEnts.deWiedadwmced theconceptthat neuropeptidescculdbeiqxztantmxlulatorsofneuronalfunctions&that specificproteolysis of pro-psptideswould~atehighly selectiveanlnwepotentpeptide ccolfigurationsthatmightbeinvolvedinlocdlandsubtleregula~ofbrainhaneostasis
422
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16 I5 14 I3 12 II ItI 9 6 7 6 5 4 3 2 I
DAYS AFTER
SURGERY
3. The mean emotionality scores of animals with septal lesions treated with saline (triangles),animals treated with Org 2766 (open circles), and control animals (filled circles) over repeated tests, starting thethirdday after surgery. From Isaacson and Poplawsky (1983).
Melanocortins,
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(de Wied, 1969, 1978). With respectto the mltiplicity of effectsof m&mocortins on adaptivebehavior,EQhus and de Wied (1980)fomlated the unifyirqmechanismthat in part is basedonneurophysiologicalfindingsthatthesepeptides increasedthearousal state in r&brain-ltiic structuresand increasedvi.gilance (seealso, de Wied and Jolles,1982). They fommlatedthehypothesis that ACTH andrelatedpeptides,bytemporarilyincreasing the stateof arousalincertainltiic systemaridlimbicsystem-relatedstructures of the brain,enhancedthem%ivationalvalue of envirormmtalstirmli. Insuch awaythepeptides may increasethe probabilityof generatingstimlus-specificresponses.
Based on thevastamuntof animaldata sugyestingthatmalanocortinsfacilitatebehavioral adaptationby improvingmotivationand attention,a varietyof studieshave been performedinvestigating the behavioralprofileof these peptidesin human volunteersand patients. Althoughour presentknmledge onthe effectiveness ofm&mccortins inhuman behavioralperfonmnce is far frun omplete, a picturemerges that shcws a surprisingly gocd coherencewithwhatiskrmmas thesepeptidesin animalstudies. Thus,despitethe relativelysmall number of studies,fraqents of ACI'Hand MSH seem to affecthuman EM; activitywhen recordedduring stkmlation or information processing(Rmncomiec, 1981). Interestingly, Gaillard (1981)ascribesthe irqrovemsntinperformanceofvollluteers during amnotonous serialtestsituationto apeptide effectcmtask-orientedmScivationor sustainedattention. Hence,thereisaresemblanceintheinterpretationofboththeanimal ardhmrandata. Althoughthe effectsof melanccortins on hman behaviorare mdest, they myhave sans advantageover presentlyavailablepsycho-stimulants inthattheyhave fewer adversiveside effects. In view of the hman behavioralprofileard the neumtmphicpropertiesofmalanocortins, it is expectedthatsuchpeptidesrrayexertbermeficialeffects onnrantalperfomanceof the agedhmanbeing. Recently,a nh of excellent reviewshave addressedtherole of ACTHlike peptidesin elderlyanimalsand paople (Pigacheand tigter,1981; Branconnier, 1981). Bnployinga serialreactiontine test in mildly senilesubjects,Branconnieret al. (1979) fourdthattreatmntwithACEi &~~~~ression of increasedreactiontimes resultingfmn continuousperf Furthemmre, the subjectsdisplayed reduceddepressionand confusion. This latteraspectof the subchronicpeptidetreatnwt is of interestas variousauthorshave reportedthat chronictreatmentof elderlyand/or nuderatedemsntedhuman beingswith Grg 2766 reducedanxietyand depressionand enkmced feelingsof cunpatenceand made the patientssore sociable (deWied and Jolles,1982). Again there seems a parallelwith the animal data, as it has been reportedpreviouslythat kxxeases the nmber of socialcontactsamong rats (Beckwith et al., 1977;File, -41979;&?esinkmd Van F&e, 1983; Spruijt,1985). 7. Conclusions In view of the well-dccmentedeffects ofmalanocortinsonneuralandbehavioral plasticityinanimals, it is appropriatetoconsidertheirpotentialityinhumandiseasesrelated to loss of brain plasticityand which are manifestwith inueasingage (GispenanddeWied, 1984). At presentlittleinformationis availableon possibleamlioratingeffectsof lsGmoco~treatlsantofpatientswithdiseases suchasseniledemntiaoftheAlshei.mr's type. The data so far seem to indicateonly small, if any, inprovenmtsofthediseased subjectsaftertreatmsntwithmsl.anoco&ns. lhemajorprablsrnwithclinicaltestingof thesenrm_~cpeptidesderivedfrrrnACTHandMSHisdesigningaproper~~tschedule (route,dose,period,etc.)andthechoiceof*prqergroupofpatients. Especiallywith reqect of the modest,but specific,mdulatory effectof melanocortins on brain and behavior,it may be that beneficialeffectsmight be producedonly if tipaptides aregiven dmingtheveryearlyphasesofthebrainpatiology. Ashasbeenstressedbynearlyall , early and specificdiagnoses con~aq scientistsin the field of age-relateddiseases are prerequisites for furtheringaurinsightin thediseaseprccess. I+rthermore, there is agrawingbodyofLiteraturedarrmstratingadiversi~withintheAlzheuner'sdisease cateqxy,perhaps thenrxtdevastatingbeing thatwithauearlyonset (Mayeuxetal.,1985). Tbeseckervations furtherunderscoretheurgentneed for as earlyadiagnosis as possible fortheage-relateddfmantias.
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Grg i766.anda-MSH.onreversallearningof rats with bilateralmlesions of the parafasciculararea. BminRss.Bull.,inpress.