Rev. Bras. Anestesiol. vol.66 número5

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

SCIENTIFIC

ARTICLE

The

effects

of

memantine

on

recovery,

cognitive

functions,

and

pain

after

propofol

anesthesia

Ulku

Emik,

Yusuf

Unal,

Mustafa

Arslan

_,

_Cengiz

_Bekir

_Demirel

DepartmentofAnesthesiologyandReanimation,SchoolofMedicine,GaziUniversity,Ankara,Turkey

Received15December2014;accepted10March2015 Availableonline20January2016

KEYWORDS

Memantine; Anesthesia; Recovery; Propofol; POCD

Abstract

Objectives: Postoperativecognitivedysfunctionreferstotheproblemsassociatedwiththought

andmemorythatareoftenexperiencedaftermajorsurgery.Theaimofthisstudyistoevaluate theeffectsofintraperitoneallyadministeredmemantineonrecovery,cognitivefunctions,and painafterpropofolanesthesia.

Methods:The study was conducted in GaziUniversity Animal ResearchLaboratory, Ankara,

TurkeyinJanuary2012.Twenty-fouradultfemaleWistarAlbinoratsweighing170---270gwere educatedfor300sintheradialarmmaze(RAM)overthreedays.GroupPwasadministered 150mgkg−1 _{ofintraperitoneal(IP)propofol;Group Mwasgiven 1mgkg}−1 _{ofIPmemantine;}

and Group MPwas given 1mgkg−1 _{of IPmemantinebefore being administered 150mgkg}−1

of IP propofol.The controlgroup received only IPsaline. RAM and hot plate values were obtained afterrecoveryfromthegroups thatreceivedpropofolanesthesiaand30minafter theadministrationofdrugsinothertwogroups.

Results:The duration of recovery for Group MP was significantly shorter than Group P

(p<0.001),and thenumber ofentriesand exits inthe RAMby Group MP was significantly higherduringthefirsthourwhencomparedtoGroupP(p<0.0001).Hotplatevalues,onthe otherhand,werefoundtobesignificantlyincreasedinallgroupswhencomparedtothecontrol values,asidefromGroupC(p<0.0001).

Conclusion: Inthisstudy,memantineprovidedshorterrecoverytimes,bettercognitive

func-tions,andreducedpostoperativepain.Fromthisstudy,wefindthatmemantinehasbeneficial effectsonrecovery,cognitivefunctions,andpainafterpropofolanesthesia.

©2015SociedadeBrasileiradeAnestesiologia.Publishedby ElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗_{Correspondingauthor.}

E-mails:[email protected],[email protected](M.Arslan). http://dx.doi.org/10.1016/j.bjane.2015.03.002

PALAVRAS-CHAVE

Memantina; Anestesia; Recuperac¸ão; Propofol; DCPO

Efeitosdamemantinasobrearecuperac¸ão,func¸õescognitivasedorapósaanestesia compropofol

Resumo

Objetivos: Adisfunc¸ãocognitivanopós-operatóriorefere-seaproblemasassociadosao

pensa-mentoeàmemóriaquesãofrequentementemanifestadosapósumacirurgiadegrandeporte.O objetivodesteestudofoiavaliarosefeitosdamemantinaadministradaporviaintraperitoneal sobrearecuperac¸ão,func¸õescognitivasedorapósaanestesiacompropofol.

Métodos: OestudofoirealizadonoLaboratóriodePesquisacomAnimaisdaUniversidadede

Gazi,Ankara,Turquia,emjaneirode2012.Vinteequatroratosalbinosdosexofeminino, adul-tos,dalinhagemWistar,pesando170-270g,foramtreinadosdurante300segundosnolabirinto radialdeoitobrac¸os(LRB)durantetrêsdias.OGrupoPrecebeu150mg/kg−1_{depropofolpor}

viaintraperitoneal(IP);oGrupoHrecebeu1mg/kg−1_{dememantinaIPeoGrupoMPrecebeu}

1mg/kg−1 _{dememantinaIPantesdaadministrac¸ãode 150mg/kg}−1 _{depropofolPI. Ogrupo}

controlerecebeuapenassoluc¸ãosalinaIP.OsvaloresdoLRBedaplacaquenteforamobtidos apósarecuperac¸ãodosgruposquereceberampropofole30minutosapósaadministrac¸ãodos fármacosnosoutrosdoisgrupos.

Resultados: Otempoderecuperac¸ãodoGrupoMPfoisignificativamentemenorqueodoGrupo

P(p<0,001),eonúmerodeentradasesaídasdoLRBdoGrupoMPfoisignificativamentemaior duranteaprimeirahora,emcomparac¸ãocomoGrupoP(p<0,0001).Osvaloresdaplacaquente, poroutrolado,foramsignificativamentemaioresemtodososgrupos,emcomparac¸ãocomos valoresdogrupocontrole,excetopeloGrupoC(p<0,0001).

Conclusão:Nopresenteestudo,memantinaproporcionoutemposmaiscurtosderecuperac¸ão,

func¸õescognitivasmelhoresereduziuadornopós-operatório.Apartirdesteestudo, desco-brimosqueamemantinatemefeitosbenéficossobrearecuperac¸ão,func¸õescognitivasedor apósanestesiacompropofol.

©2015SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este ´eum artigoOpen Accesssobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Postoperative cognitive dysfunction (POCD) refers to dis-orders affecting attention, consciousness, orientation, perception,judgment,andinsightthatdevelopduringthe postoperativeperiod.AlthoughtheetiologyofPOCDhasyet tobeadequatelyexplained,manyfactorshavebeenfound toberesponsible.Mostrecently,disequilibriuminthe neu-rotransmittersystemsduringthepreoperativeperiod,such asacetylcholine,serotonin,glutamate, andaspartate,has beenoneofthemostcommonlyblamedfactors.1---3

The effects of the nicotinic system on learning, mem-ory, and cognition have been shown in studies of both humans and animals.4 _{This directly influences attention}

while also affecting learning and memory by facilitating acetylcholine,glutamate, dopamine, noradrenaline, sero-tonin,andgamma-aminobutyricacid(GABA)releasesfrom thepresynapticnicotinicacetylcholinereceptors(nAChRs).4

Propofolisafrequentlyusedhypnoticagentthatworks by potentializing the chloride flow of GABA by connect-ingtothe ␤-subunitin theGABA receptor.The alphaand gamma(␥2)subunits alsoseemtocontribute tothe

mod-ulationoftheeffectofpropofolontheGABAreceptor.As aresultof this effectontheGABAA receptorsin the

hip-pocampus,propofolinhibitsAChreleaseinthehippocampus andprefrontal cortex. This seems tobesignificant in the sedativeeffectsofpropofol.Propofoldiffusesinhibitionon N-methyl-d-aspartate (NMDA)which is a subtype of

gluta-matereceptor, by modulatingthe gate mechanism in the sodiumchannelsandthuscontributingtothecentralnervous

system(CNS)effects.PropofolisalsoeffectiveontheGABAA

andglycinereceptorsonthedorsalhornofthespinalcord, andmodulationofthesereceptorsisknowntoresultin cog-nitivedysfunction.Propofolisreportedtoinhibitcognitive functionsforupto6h.5,6

Memantine is a non-competitive receptor antagonist with a low affinity that inhibits the pathological activa-tionofNMDAreceptorswithoutchangingtheirphysiological functions.7 _{Memantine has demonstrated an ability to}

reverse the changes that develop in the synaptic plastic-ityofanimalmodelsafteritsusewassuggestedforvarious neurologicaldisorders.8 _{Theuseofmemantinehasyielded}

positiveresultsonlearning,memory,pain,and neuroprotec-tiveeffectsinclinicalstudies.9_{Asaresult,itwassenttothe}

FoodandDrugAdministration(FDA)in2003forapprovalfor thetreatmentofAlzheimer’sdisease.Therehavealsobeen studiesinvestigatingtheuseofmemantineinthetreatment of chronicpain,10 _{in whichit hasbeenshown todecrease}

diabeticneuropathypaininrats.11

Inthepresentstudy,theeffectsofmemantine adminis-tration priortopropofolanesthesiaonrecovery,cognitive functions,andacutepainareevaluated.

Materials

and

methods

Animalsandexperimentalprotocol

oftheExperimentalAnimalsEthicsCommitteeofGazi Uni-versity.Alloftheprocedureswereperformedaccordingto theacceptedstandardsoftheGuidefortheCareandUseof LaboratoryAnimals.

Twenty-four adult female Wistar Albino rats weighing 170---270g were used. The rats were kept in lightened and darkened mediums for alternating 24h periods until the beginning of the study to allow them to adapt to the medium. The subjects wereleftin a light- and heat-standardized medium and fed with standard pellet feed. Therewasnorestrictiononaccesstowater;however,the ratsweredeprivedoffoodfor2hbeforethestudy.

Allratswereweighedandtheresultswererecordedfor all groups. After being deprived of food for 2h prior to thestudy,pellet food wasplaced at theend ofeach arm of a radial arm maze (RAM). The rats were educated in the RAM for 300s over the first three days of the study, and the entry and exit times of the rats at the arms of theRAMwererecorded.The RAMandhotplatebasal val-ues were measured for all rats on the fourth day of the study,afterwhichtheratswererandomlyallocatedintofour groups.

GroupC(Controlgroup,n=6):eachratwasadministered 1mlof0.9%sodiumchloride(saline)intraperitoneally(IP). RatswereplacedintheRAM30minaftertheadministration of saline IP, and the entry andexit times at the arms at beginningT0,1h(T1),and2h(T2),aswellasthedurations

onthehotplate,weremeasuredandrecorded.

Group M (Memantine group, n=6): 1mgkg−1 _dose

of memantine (memantine hydrochloride, Sigma---Aldrich Chemie,St.Louis,MO,USA)in1mlsalinewasadministered IP.Thirty minutesafterthe administrationof memantine, theratswereplacedintheRAM.Theentryandexittimes atthearmsatT0,T1,andT2,andthedurationsonthehot

plate,weremeasuredandrecorded.

Group P (Propofol group, n=6): 150mgkg−1 _{dose of}

propofol1%(propofol1%,FreseniusKabiAB,Germany)was administeredIP andthe application timewasrecordedin allrats. The rats werelefttorecover,then recovery was evaluatedwithatailpinchtest(squeezingthetail3---4cm fromthebasefor 30s using‘‘rubberdam’’forceps)12 _and

thetimeforrecoverywasrecorded.Theratswereplacedin theRAMafterrecovery.Thefirstmeasurementafter recov-erywasrecordedas0(T0)hour,afterwhichthefirsthour

(T1)andsecondhour(T2)measurementswereobtainedand

recorded.

GroupMP(Memantine+propofolgroup,n=6):1mgkg−1

dose of memantine was applied IP and 30minutes later 150mgkg−1 _{of propofol wasinjected IP.Propofol}

applica-tion time wasrecorded in all rats. The rats were left to recover,recoverywasevaluatedwithatailpinchtest,and thetimeforrecoverywasrecorded.Theratswereplacedin theRAMafterrecovery.Thefirstmeasurementafter recov-erywasrecordedas0(T0)hour,afterwhichthefirsthour

(T1)andsecondhour(T2)measurementswereobtainedand

recorded.

Theradialarmmaze

The radialarm maze is comprised of a Plexiglass central platformmeasuring30cmwitheightequidistantarms radi-atingoutwards(forexample,80cm×12.5cm)withaheight

of66cm.The areasaroundthemazearevisibletopermit theorientationofrats,andratsmoveusingthosetips.For thisstudy,theRAMwasplacedonatabletop90cmfromthe floor.

Hotplatetestforacutepainevaluation

The aluminum hot plate surface was heated up to 55◦_C. Glasscylinderswereusedtoensurethattheratsremained intheheatedregionwhilenotlimitingcapacityfor move-ment.Movementssuchasfootraising,jumping,licking,and walkingbackwardswere allaccepted aspositive,andthe times from first placement until the first positive move-mentwererecorded.Thetestwasterminatedafter25sto preventtissuedamage.

Statistical

analysis

AstatisticalevaluationwasperformedusingtheSPSS12.0 computer program utilizing the following tests. Statisti-cal analysis data was presented as the mean±standard deviation (minimum---maximum); p<0.05 wasaccepted as significant inall statistical analyses; andp<0.033 (0.1/3) valuewasacceptedassignificantinevaluationsof Bonfer-ronicorrections.AKolmogorov---Smirnovtestwasperformed forthemeasurableparameterstoidentifynormalor abnor-maldistributions.

In independent groups, the differences between the groups were tested using a Kruskal---Wallis test and a Mann---WhitneyUtest,withaBonferronicorrectionusedto detectthegroupsthatgenerateddifferenceswhenanywere identified.

Results

The body weights of the subjects (g) were similar in all groups.

The timeperiodin thetail pinchtest wassignificantly shorterinGroupMPwhencomparedtoGroupP(Table1).

Thebasalmeasurementsofthehotplateweresimilarin allgroups(Table1).Thehotplatevalueswerefoundtobe significantlyincreasedinallmeasuredtimeperiodsingroups M,P,andMPwhencomparedtoGroupC.

The RAM valueswere found tobesimilarbetween the groupsonthedaysbeforetheadministrationofanesthesia (Table2).

The entry and exit times at hours T0, T1, and T2

werefoundtobesignificantlydecreased inGroupPwhen compared to Group C (p<0.0001, p<0.0001, p=0.029, respectively). Only in Group MP were the entry and exit timesatT0significantlydecreasedwhencomparedtoGroup

C(p=0.001).

TheentryandexittimesatT0andT1werefoundtobe

sig-nificantlydecreasedinGroupPwhencomparedtoGroupM (p<0.0001,p<0.0001,respectively).OnlyinGroupMPwere theentryandexittimesatT0significantlydecreasedwhen

comparedto Group M (p<0.0001), and only in Group MP weretheentryandexittimesatT1significantlydecreased

whencomparedtoGroupP(p=0.030).

Table1 Tailpinchandhotplatedataforallgroups[mean±SD(minimum---maximum)].

GroupC (n=6)

GroupM (n=6)

GroupP (n=6)

GroupMP (n=6)

p

Tailpinch(min) --- --- 229.50±25.11 (215---278)

152.20±25.13b

(125---175)

0.001

Hotplatebasal(s) 4.82±2.03 (2.3---8.2)

5.50±2.63 (3.1---9.9)

6.98±1.82 (4.6---9)

6.08±2.03 (3.6---9.5)

0.374

HotplateT0(s) 6.03±2.23

(3.3---8.6)

17.94±8.26a,c

(7.7---25)

22.98±4.94a,c

(12.9---25)

23.40±3.58a,c

(17.0---25)

<0.0001

HotplateT1(s) 5.83±1.99

(3.3---7.9)

23.98±2.95a,c

(18---25)

17.42±7.66a,c

(5.5---25)

20.00±7.87a,c

(7---25)

<0.0001

HotplateT2(s) 5.73±1.91

(3.3---7.9)

24.17±2.04a,c

(20---25)

18.67±6.65a,c

(8---25)

17.30±8.95a,c

(6---25)

<0.0001

a_{p<0.05(comparedtoGroupC).} b _{p<0.05(comparedtoGroupP).}

c _{p<0.05(comparedtohotplatebasalmeasurement).}

1. Entryandexittimeswerefoundtobesimilarbetween thefirstdaymeasurementsandothermeasurementsin GroupCandGroupM.

2. InGroupP,theentryandexittimesatT0andT1were

sig-nificantlydecreased(p=0.011,p=0.011,respectively). 3. InGroupPM,theentryandexittimesweresignificantly

reducedonlyatT0(p=0.006)(Table2).

Discussion

Thisstudyevaluatingtheeffectsofmemantineon postop-erativerecoveryandpaininratshasrevealedadecreasein recoverytimeandintherecoveryofcognitivefunctions.It wasalsofoundtobeeffectiveinthemanagementofacute pain.

A standardization of perioperative and postoperative factorsisdifficultinclinicalstudiesassociatedwith postop-erativecognitivefunctionsduetothedifferentparameters involved, includingthetypeofsurgery, thedistributionof age,theinteractionofanesthesia,thepresenceofbleeding resultingfromsurgery,andthepossibilityofinfection.While theeffectsofanesthesiaoncognitivefunctionshavebeen demonstratedinpreviousexperimentalstudies,13_thisstudy

hasadoptedtheRAMmethod,inwhichonlytheparameter oftheanestheticagentischangedandallotherfactorsare standardized.

RAMis a frequentlyusedmethod for theevaluation of cognitive functions in experimental animal models.13

Cul-leyetal.,13_{usedaRAMwith12armsinastudyevaluating}

the effects of nitrous oxideonlearning disorders in rats. As in the present study,theyalso lefttherats for 10min for three consecutive dayson the RAM tomeasure levels

Table2 Dataofentryandexitsoftheradialarmmazeinallgroups[mean±SD(minimum---maximum)].

GroupC (n=6)

GroupM (n=6)

GroupP (n=6)

GroupMP (n=6)

p

Day1(entry---exit)(s) 7.50±3.21 (2---11)

6.33±1.63 (4---8)

7.67±2.58 (5---12)

7.50±4.03 (0---11)

0.858

Day2(entry---exit)(s) 5.50±3.27 (1---11)

6.17±3.13 (3---11)

8.00±4.19 (4---15)

5.83±3.49 (0---10)

0.625

Day3(entry---exit)(s) 5.67±2.16 (2---8)

4.00±1.41 (2---6)

6.00±4.60 (0---11)

6.50±4.76 (0---11)

0.649

TimeT0(entry---exit)(s) 6.00±2.97

(3---11)

6.83±2.48 (3---10)

0.17±0.40a,b,d

(0---1)

0.00±0.00a,b,d

(0---0)

<0.0001

TimeT1(entry---exit)(s) 5.67±2.33

(3---9)

5.50±1.38 (3---7)

0.0±0.0a,b,d

(0---0)

2.60±2.07c

(0---5)

<0.0001

TimeT2(entry---exit)(s) 5.50±2.07

(3---8)

4.17±1.72 (2---7)

2.17±1.83a

(0---5)

2.40±1.52 (0---4)

0.017

a_{p<0.05(comparedwithGroupC).} b _{p<0.05(comparedwithGroupM).} c _{p<0.05(comparedwithGroupP).}

of adaptation and education,from which they were able todeducethatgeneralanesthesiareversiblyimpaired the previouslylearnedspatialmemoryinolderrats.

Postoperative cognitivedysfunctionisattributedtothe useofbothIVandinhaledanesthetics,whicharebelievedto causelong-termstructuralchangesintheCNSsincetheycan nolongerbeidentifiedinthebloodseveraldaysafter admin-istration. Anesthetic agents administered during surgery changethebehavioralstatusofthepatientandaffectbrain activity in at least two mechanisms. The first of these is described as the dose-dependent effect on the brain, andthesecondistheinhibitionofregion-specificneuronal activity, disruptionof functional relations, and disruption oftheneuralplexus.14_{Thesecomponent}

neurotransmitter-mediatedionchannels,especiallytheGABA,glutamate,and NMDAchannels,aremodulatedbymanyanestheticagents andarediagnosedastargets oftheanestheticagents and receptorsinbothsynapticandextra-synapticareas.15

Ananalysisofthepropofolusedinthisstudyrevealsthat its sedative effects are related to its potentialization of chlorideflow throughthe connectiontotheGABAA

recep-tor ␤ subunit of the hippocampus and the prevention of AChreleasefromthehippocampusandprefrontalcortex.In addition,propofolencouragesdiffuseinhibitionintheNMDA receptors,whicharethesubtypesofglutamatereceptors, bymodulatingthegatemechanismofthesodiumchannels.5

Modulation ofthesereceptors is knowntoproducePOCD; consequently,therearemanystudiesconfirmingtheroleof propofolin thedevelopmentofPOCD.Kunimatsu etal.,16

observed POCD in patients undergoingoral surgery under propofolanesthesia.Inanotherstudysupportingthisfinding, Nishikawaetal.,17 _{identifieda higherpostoperative}

delir-iumscoreinagroupofpatientswhohadbeenadministered propofol and who had been given an epidural anesthesia in their comparison of propofol, sevoflurane, and epidu-ralanesthesiain patientsundergoinglaparoscopicsurgery. Larsen et al.,18 _{conducted a study of cognitive functions}

andrecoveryafterpropofol,desflurane,andsevofluranein 60patientswithASAI---II; theresultsofthisstudy showed thatthepatientsinthepropofolgroupawokeandrecovered faster thanthosethathad beenanesthetizedwith desflu-raneorsevoflurane.Desfluraneandsevofluraneanesthesia showedsimilareffects,althoughtheeye-openingtimewas shorteramongthoseanesthetizedwithdesflurane.Inlightof thesestudies,theintentionherehasbeentocarryoutthis study using propofolanesthesia, which is knownto cause POCDandwhichallowsforearlyrecoveryfromanesthesia. Anotherreasonforchoosingpropofolastheanestheticagent wasitsmechanismaffectingthediffuseinhibitionofNMDA receptors, GABAA receptors, and ACh receptors, and the

hypothesis thattheseeffectsarereversedby memantine, whichisanNMDAreceptorantagonist.

A search of previous studies garnered no data on the effect of memantine on cognitive dysfunction following recovery from propofol anesthesia. For this reason, the intention has been to evaluate the effects of memantine afterrecoveryfrompropofolanesthesiaoncognitive func-tions andpain in arat modelwith aminimal variationin variablesandwithasinglevariableparameterusingpropofol astheanestheticagent.

Memantine,aNMDAantagonist,wasfirsttestedon ani-malmodelsbyBigamous,whodemonstratedimprovements

in cognitive functions and deficits in neuron plasticity.19

Memantine is a NMDA receptor antagonist that is a non-dissociative anesthetic. It features rapid channel opening kinetics and is a powerful voltage-dependent channel blocker with a lesser affinity to the NMDA receptor channel.20 _{IncontrasttootherNMDA receptorantagonists}

withdissociative anestheticeffects,it hasdifferent phar-macologicalproperties.Thisuniquepropertyofmemantine allowsittoactivatepathologicalNMDAreceptors,while hav-ingnoeffectonthephysiologicalNMDAreceptorsthathave acriticalroleinmemoryandlearning.21

Memantine was approved for the treatment of Alzheimer’sdiseasebyEuropeanmedicines Agency(EMEA) inEurope in 2002and by theFDA in the UnitedStates in 2003.8_{Sincethen,memantinehasbeenshown toimprove}

performanceinstudiesofvariouspharmacologicallearning andmemorymodelsandwasfoundtobeusefulinpatients with Alzheimer’s disease.22 _{The effect of memantine on}

cognitivefunctionsincasesofneurodegenerativediseases, suchasAlzheimer’s,is studied usingdifferent application methodsandindifferentdoses.Anacuteadministrationof memantinein a5mgkg−1 _{dose had noeffectonbehavior}

or motor functions23_{; however, the administration of a}

10mgkg−1 _{dose resulted in hyperlocomotion and}

deterio-ration in a ‘‘food-motivated task’’ test. A single dose of 20mgkg−1_{ofmemantinecausesataxia.}24,25

When memantine was administered in 10mgkg−1 _and

20mgkg−1 _{doses prior to the learning period in a}

pas-sive avoidancetest, it was shown to deterioratelearning behavior and deter memory.26 _{These results suggest that}

memantine produces beneficial results in low doses but has harmful effects on behavior in high doses.27 _{In a}

study that involved the administration of donazepil and rimonabant, which are known to cause cognitive disor-ders,learningbehaviorsweretestedusingRAM.Memantine doses of 0.1mgkg−1_{, 0.3mgkg}−1_{, and 0.56mgkg}−1 _were

foundto decreaseerrorsin the RAM test; however,doses of 1.0mgkg−1_{, 3.0mgkg}−1_{, and10mgkg}−1 _{werefound to}

increasedeficits.28

The present study involved the administration of 1mgkg−1 _{IP dosesof memantine; however,the effects of}

otherdosescannotbepredicted,anda similarstudy with differentdosesofmemantineshouldbeperformed.

Generally,recoveryfromanesthesiaisdeterminedbythe rate at which the anesthetic agentconcentrations in the braintissuedecrease,andtheeliminationrateofthedrug.29

Itcanbededucedfromthepresentstudythatearlyrecovery frompropofolanesthesia,whichwasthecaseinthisstudyin memantine-administeredrats,isduetothecommon inter-actionofbothagentsontheNMDAreceptorratherthanto anincreaseintheeliminationrate.Inastudysupportingthe effectofthisinteractiononthelevelofanesthesia,Brosnan etal.,30_{usedpicrotoxin,whichisaGABA}

Areceptor

studybyKurodaetal.,31_{ontheeffectsoftheNMDAreceptor}

antagonistdizocilpine on isofluraneMAC, the MK-801 was foundtodecreaseisofluraneMACduetothereceptor inter-actionthroughGABA.

ThisstudyhasalsoanalyzedtheeffectsofNMDA recep-torantagonistsoncognitivefunctions.Whenthecognitive functions were analyzed on the RAM configuration in 1-hourintervalsafterawakening,nosearchingmovementwas observedintheratsthathadbeenadministeredonly propo-fol; however, searching movementswere observed during thefirsthourinGroupMP(p<0.0001).Searchingmovements startedinthepropofolgroupduringthesecond hour,with nonoticeabledifferences between thegroups. In a study toevaluatecognitiverecoverythroughaseriesoftestsof attentionspan,planning,latememory,andspeech,Sanou etal.,6 _{found that cognitiverecovery frompropofol took}

between 1 and 3h following general anesthesia and that recoverytoapre-anestheticstatetook6h.Marshalletal.,32

inasimilarstudyofpropofolandalfentanil,foundthat lev-elsofwordmemorywere decreasedfor 5h. Althoughthe laststudywasperformedonhumans,recoveryfrompropofol inourstudystartedduringthefirsthourinthe memantine-administeredratsandduringthesecondhourintheratsthat hadnotbeengivenmemantine.Measurementsinthisstudy werelimitedto2hafterrecoveryfromanesthesia,meaning thatthetimeneeded toreacha pre-anestheticstate was notevaluated.

Itcanbededucedfromthisstudy thatNMDAreceptors playasignificantroleintheformationofneuronalnetworks during memory, learning, and development in the mam-malian brain.Sincethis takesplacein some physiological functions, such assynaptic plasticity and synapsis forma-tion,thereceptorsarebeneficialin explainingPOCD.This studyhasrevealedthattheadministrationofmemantineis beneficialintherecoveryofcognitivefunctionsafter anes-thesia.

Anothersubjectofourstudywastheeffectof meman-tineonacutepain.Grandeetal.33_{haveshowninaclinical}

study that memantine is effective in eliminating neuro-pathic pain in patients after a metastatic spinal tumor resection.11,33_{Thepotentialusesofmemantineinthe}

treat-mentof chronic andneuropathicpain raisedthe question of whether it may also be effective in the treatment of stress-relatedpain.Thehotplatemethod,withastandard heatof52◦_{C,wasusedtoadministeracutepain,andthe} measured basal pain levels before the administration of memantineweresimilarinallgroups.Serialmeasurements at1-hourintervalsweretaken,fromwhichitwas demon-stratedthatthedurationofpainresponseinthememantine, propofol, and memantine+propofol-administered groups were significantly longer when compared to the basal values in each group and when compared to the con-trol group (p<0.0001); however, there was no significant differencebetweenthememantine,propofol,and meman-tine+propofol-administered groups. This clinical picture revealsthatmemantine isalsoeffective inthe treatment ofacutepain.Aspropofolisalsoknowntohavesome anal-gesicproperties,5 _{thismayexplainthesimilarity between}

thegroups.

Inthestudydesign,theratswerepermittedtostay on thehot platefor a maximum of 25s when evaluatingthe analgesic effects of the drugs, which meant that it was

notpossibletoidentifywithanycertaintywhether propo-fol andmemantinepossessanyadditiveanalgesic effects. Nointerpretationwaspossiblesincethetimesofthethree groupsweresimilar.Astheanalgesiceffectswerefollowed upforonly2h,theeffectsofthedrugsonanalgesiatimes could not be evaluatedclearly. In a study evaluating the effectsof memantineonacutepain,Parketal.34

demon-stratedthatmemantine,giveninanIPdoseof10mgkg−1₍₁₀

timesthedoseusedinourstudy)30minbeforeperforming a trigeminocervical pain modelwith a formalininjection, resulted in a decrease in pain scores. In contrast to the present study, in a study of rats by Zhan and Brennan,35

in whichmemantinewasusedfor postoperativepain con-trol,plantarincisionswereproducedinratsandmemantine was appliedintrathecally through an intrathecal catheter withnobeneficialresults.Inacomparativestudyto evalu-atethelocalanestheticeffectsofmemantine,Chenetal.,36

suggestedthatmemantineproducedbetterlocalanalgesic effectswhencomparedtolidocaineandthatNMDA recep-torscontributedtothisanalgesiceffect.

Conclusion

Intraperitonealmemantineadministrationinratsbeforethe administrationofpropofolanesthesiawasobservedto facil-itaterecoveryfromanesthesiaandtohavepositiveeffects oncognitivefunctionsandacutepain.Thissubjectmay ben-efitfromfurtherevaluationinfuturestudies.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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