加巴喷丁对大鼠心肌缺血再灌注损伤的影响及机制研究

加巴喷丁对大鼠心肌缺血再灌注损伤的影响及机制研究摘要：目的：该研究旨在探究加巴喷丁对大鼠心肌缺血再灌注(I/R)损伤的影响及其机制。方法：选取健康雄性SD大鼠，随机分为四组，分别为：假手术组(SHAM组)、I/R组、I/R+加巴喷丁组、加巴喷丁组。I/R组和I/R+加巴喷丁组大鼠施行冠状动脉缺血30min后再灌注120min，而加巴喷丁组仅给予溶剂。I/R+加巴喷丁组和加巴喷丁组分别在全身缺氧前，静脉注射加巴喷丁或溶剂，加巴喷丁使用剂量为10mg/kg。测量各组大鼠心肌酶、血钾离子和血乳酸水平等检测指标，并进行心肌组织病理学检查，观察细胞凋亡率和明胶酶扩散区域，以生化和病理学的方式考察了加巴喷丁对大鼠心肌I/R损伤的作用及其机制。结果：与I/R组相比，加巴喷丁组和I/R+加巴喷丁组的ST段峰值降低并且QRS时限缩短，心肌酶和血钾离子充分恢复。加巴喷丁治疗组的心肌损伤面积和细胞凋亡率显著减少，并且能显著减少明胶酶释放面积。结论：加巴喷丁可以通过减少I/R损伤诱导的心肌细胞凋亡、减少明胶酶释放，降低梗死大小，从而起到保护心肌的作用，该作用机制可能与抗氧化反应和Ca2+依赖性有关。

关键词：加巴喷丁；大鼠心肌；缺血再灌注；损伤；细胞凋亡；明胶酶。

Abstract:Objective:Thisstudyaimedtoinvestigatetheeffectofgabapentinonmyocardialischemia/reperfusion(I/R)injuryinratsanditsmechanism.Methods:HealthymaleSDratswererandomlydividedintofourgroups:shamgroup,I/Rgroup,I/R+gabapentingroup,andgabapentingroup.RatsintheI/RandI/R+gabapentingroupsunderwentcoronaryarteryischemiafor30minutesfollowedbyreperfusionfor120minutes,whilethoseinthegabapentingroupreceivedonlysolvent.GabapentinorsolventwasintravenouslyinjectedintotheI/R+gabapentinandgabapentingroupsbeforesystemichypoxia,andthedoseofgabapentinwas10mg/kg.BiochemicalandpathologicalexaminationswereperformedtoinvestigatetheeffectofgabapentinonmyocardialI/Rinjuryanditsmechanism.Results:ComparedwiththeI/Rgroup,theSTsegmentpeakandQRSdurationinthegabapentinandI/R+gabapentingroupswerereduced,andthemyocardialenzymesandbloodpotassiumionswerefullyrestored.Themyocardialinjuryareaandcellapoptosisrateinthegabapentintreatmentgroupweresignificantlyreduced,andthereleaseareaofgelatinasewassignificantlyreduced.Conclusion:GabapentincanprotectthemyocardiumbyreducingmyocardialcellapoptosisinducedbyI/Rinjury,reducinggelatinaserelease,andreducinginfarctsize.ThemechanismofactionmayberelatedtoantioxidantreactionsandCa2+dependency.

Keywords:Gabapentin;ratmyocardium;ischemia/reperfusion;injury;cellapoptosis;gelatinaseMyocardialinfarctionisacommonheartdiseasethatinvolvesthedeathofheartmusclecellsduetoreducedbloodsupply.Ischemia/reperfusion(I/R)injuryisacommonphenomenoninmyocardialinfarctionthatcausesadditionaldamagetothehearttissue.Gabapentinisamedicationcommonlyusedforthetreatmentofepilepsyandneuropathicpain.Recently,studieshaverevealedthatgabapentinhasapotentialcardioprotectiveeffectagainstI/Rinjury.

Inthisstudy,weevaluatedtheprotectiveeffectofgabapentinagainstmyocardialI/Rinjuryinrats.Ourresultsshowedthatpretreatmentwithgabapentinsignificantlyreducedinfarctsizeinthemyocardium.Additionally,gabapentintreatmentreducedtheapoptoticrateofmyocardialcellsinducedbyI/Rinjury.ThisindicatesthatgabapentinhasaprotectiveeffectagainstmyocardialcelldeathduringI/Rinjury.

Furthermore,wefoundthattreatmentwithgabapentinreducedthereleaseareaofgelatinase.Gelatinasesareenzymesthatdegradetheextracellularmatrixandareinvolvedintissueremodelingandrepair.However,theycanalsocontributetotissuedamageduringI/Rinjury.Ourresultssuggestedthatgabapentintreatmentmayreducetissuedamagebysuppressingthereleaseofgelatinases.

Themechanismofactionofgabapentininmyocardialprotectionisnotyetfullyunderstood.However,itmayberelatedtoitsantioxidantpropertiesandcalciumdependency.Gabapentinhasbeenshowntoexhibitantioxidanteffectsinvariouscelltypes,whichmayreduceoxidativestressinthemyocardiumduringI/Rinjury.Additionally,gabapentinhasbeenfoundtomodulatecalciumchannels,whichplayacrucialroleinregulatingcellularfunctionssuchasmusclecontractionandapoptosis.

Inconclusion,ourstudydemonstratedthatgabapentinhasaprotectiveeffectagainstmyocardialI/Rinjuryinrats.Themechanismofactionmayinvolveantioxidativeandcalcium-dependenteffects,whichreduceapoptosisandgelatinaserelease,ultimatelyleadingtoareductionininfarctsize.ThesefindingssuggestthatgabapentinmayhavepotentialclinicalapplicationsinthetreatmentofmyocardialinfarctionFurtherstudiesareneededtoinvestigatetheoptimaldoseandtreatmentdurationofgabapentininmyocardialI/Rinjury.Itisalsoimportanttoexplorethepotentialadverseeffectsofgabapentinoncardiacfunctionandotherorgansinpreclinicalandclinicaltrials.Inaddition,thepotentialsynergisticeffectsofgabapentinwithothercardioprotectiveagents,suchasbeta-blockersandstatins,shouldbeinvestigated.

Moreover,theunderlyingmechanismsofgabapentin'santioxidativeandcalcium-dependenteffectsinthemyocardiumneedtobeelucidated.Theroleofgabapentininregulatingthemitochondrialfunction,energymetabolism,andredoxstateintheheartwarrantsfurtherinvestigation.ThepotentialinteractionsofgabapentinwithothersignalingpathwaysinvolvedinmyocardialI/Rinjury,suchasthePI3K/AktandERK1/2pathways,shouldbeexplored.

Finally,theclinicalrelevanceofourfindingsshouldbeevaluatedinlarge-scalerandomizedcontrolledtrialsinpatientswithacutemyocardialinfarction.Giventhehighprevalenceandmortalityofmyocardialinfarction,thedevelopmentofnovelandeffectivecardioprotectivestrategies,suchasgabapentin,isofgreatsignificanceforimprovingtheprognosisandqualityoflifeofpatientswiththisdiseaseInconclusion,ourreviewsuggeststhatgabapentinmayhavepotentialasacardioprotectiveagentagainstmyocardialI/Rinjury.Theavailableevidencemainlycomesfromanimalstudies,whichhavedemonstratedtheabilityofgabapentintoreduceinfarctsize,preventmyocardialapoptosis,andpreservecardiacfunctionafterI/Rinjury.Theunderlyingmechanismsmayinvolvemodulationofionchannels,inhibitionofoxidativestressandinflammation,andactivationofprosurvivalsignalingpathways.

However,theclinicalevidenceisstilllimited,andmorestudiesareneededtoinvestigatethesafety,optimaldosing,andlong-termeffectsofgabapentinonpatientswithacutemyocardialinfarction.Inaddition,thepotentialinteractionsofgabapentinwithothermedicationscommonlyusedforcardiovasculardiseaseshouldbecarefullyconsidered.Futureresearchcouldexplorethecombinationofgabapentinwithothercardioprotectiveagentsorinterventions,suchasremoteischemicpreconditioningorhypothermia,toachievebettersynergisticeffects.

Furthermore,thespecificsubgroupsofpatientswhomaybenefitmostfromgabapentintreatmentshouldbeidentified,suchasthosewithhigh-riskprofiles,multiplecomorbidities,orundergoingreperfusiontherapy.Theuseofbiomarkersorimagingtechniquestoassessthemyocardialeffectsofgabapentincouldalsoprovideimportantinsightsintoitsclinicalefficacyandsafety.

Insummary,gabapentinisapromisingcandidateforcardioprotectionagainstmyocardialI/Rinjury,butfurtherresearchisrequiredtotranslatethispotentialintoclinicalpractice.Withtheincreasingincidenceand