RIP1-RIP3-MLKL通路介導的程序性壞死在顱內海綿狀血管瘤并發(fā)癲癇的相關發(fā)病機制中的研究

RIP1-RIP3-MLKL通路介導的程序性壞死在顱內海綿狀血管瘤并發(fā)癲癇的相關發(fā)病機制中的研究摘要:

顱內海綿狀血管瘤(cavernousmalformation,CCM)是一種重要的神經血管疾病，其主要的臨床表現是發(fā)作性頭痛、癲癇、神經系統(tǒng)缺陷和出血等癥狀。引起CCM血管內皮細胞凋亡及血管泄漏的病理機制尚未完全闡明。近期研究發(fā)現，在CCM并發(fā)癲癇的病理生理機制中，程序性細胞死亡(necroptosis)發(fā)揮了重要的作用。本文回顧了近年來關于RIP1/RIP3/MLKL通路介導的程序性壞死在CCM并發(fā)癲癇的相關研究，分析了該通路在CCM發(fā)病機制中的作用。同時，本文還探討了針對該通路的藥物干預在CCM治療中的應用前景。

關鍵詞:顱內海綿狀血管瘤；癲癇；程序性死亡；RIP1/RIP3/MLKL通路；治療

Abstract:

Cavernousmalformation(CCM)isanimportantneurologicalvasculardisease,whichismainlymanifestedasparoxysmalheadache,epilepsy,neurologicaldefectsandhemorrhage.ThepathologicalmechanismofcausingapoptosisofendothelialcellsandvascularleakageinCCMhasnotbeenfullyelucidated.RecentstudieshavefoundthatnecroptosisplaysanimportantroleinthepathophysiologicalmechanismofCCMcomplicatedwithepilepsy.ThispaperreviewstherecentresearchonRIP1/RIP3/MLKLpathway-mediatednecroptosisinCCMcomplicatedwithepilepsy,analyzestheroleofthispathwayinthepathogenesisofCCM,andexplorestheapplicationprospectofdruginterventiontargetingthispathwayinthetreatmentofCCM.

Keywords:Cavernousmalformation;epilepsy;programmeddeath;RIP1/RIP3/MLKLpathway;treatmenCavernousmalformation(CCM)isavasculardisordercharacterizedbythepresenceofabnormalbloodvesselsinthebrain,whichcanruptureandcausebleeding,seizures,andneurologicaldeficits.EpilepsyisoneofthemostcommonsymptomsofCCM,affectingupto60%ofpatients.DespiterecentadvancesinourunderstandingofthegeneticandmolecularmechanismsunderlyingCCM,effectivetreatmentsforthisconditionarestilllacking.

Necroptosis,aformofprogrammedcelldeath,hasbeenimplicatedinvariousneurologicaldisorders,includingepilepsy.Recently,studieshaveshownthattheRIP1/RIP3/MLKLpathway-mediatednecroptosisplaysanimportantroleinthepathophysiologicalmechanismofCCMcomplicatedwithepilepsy.

RIP1andRIP3arekinasesthatarerecruitedtothenecrosome,acomplexthatformsinresponsetocellularstress,andphosphorylateMLKL,akeyexecutionerofnecroptosis.Activationofthispathwayleadstotheformationofplasmamembranepores,whichcausethereleaseofintracellularcontentsandtriggeraninflammatoryresponse.

SeveralstudieshavedemonstratedtheupregulationofRIP1/RIP3/MLKLpathwayinCCMlesionsandthesurroundingbraintissue,aswellasinthecerebrospinalfluidofpatientswithCCMcomplicatedwithepilepsy.Moreover,geneticorpharmacologicalinhibitionofthispathwayhasbeenshowntoamelioratetheneurologicalsymptomsandreducethesizeofCCMlesionsinanimalmodels.

Therefore,targetingtheRIP1/RIP3/MLKLpathwaymayrepresentapromisingapproachforthetreatmentofCCMcomplicatedwithepilepsy.Severaldrugshavebeendevelopedthatcaninhibitkeycomponentsofthispathway,suchasnecrostatin-1andGSK’872.However,furtherstudiesareneededtodeterminethesafetyandefficacyofthesedrugsinhumanpatientswithCCM.

Inconclusion,theRIP1/RIP3/MLKLpathway-mediatednecroptosisplaysacrucialroleinthepathogenesisofCCMcomplicatedwithepilepsy.TargetingthispathwaymayoffernewopportunitiesforthedevelopmentofeffectivetherapiesforthisdisorderSeveralotherpotentialtherapeutictargetsforCCMhavealsobeenidentified.Oneoftheseistheangiopoietin-Tie2signalingpathway,whichhasbeenshowntoregulateangiogenesisandvascularremodeling.Studieshavefoundthatthelevelsofangiopoietin-2(Ang-2),aligandoftheTie2receptor,areelevatedinhumanCCMlesionsandinanimalmodelsofthedisease.InhibitionofAng-2hasbeenshowntoreducelesionburdenandimproveneurologicaloutcomesinmousemodelsofCCM.

AnotherpotentialtherapeutictargetisHIF-2α,atranscriptionfactorthatregulatesgenesinvolvedinangiogenesisandvascularremodeling.HIF-2αlevelshavebeenfoundtobeelevatedinhumanCCMlesionsandinmousemodelsofthedisease.InhibitionofHIF-2αhasbeenshowntoreducelesionburdenandimproveneurologicaloutcomesinmousemodelsofCCM.

Inaddition,recentstudieshaveidentifiedapotentialroleforimmunecellsinthepathogenesisofCCM.Specifically,inflammatorymacrophagesandTcellshavebeenfoundtobepresentwithinCCMlesions.InhibitionoftheseimmunecellshasbeenshowntoreducelesionburdenandimproveneurologicaloutcomesinmousemodelsofCCM.

Overall,thedevelopmentofeffectivetherapiesforCCMwillrequireabetterunderstandingofthemolecularmechanismsunderlyingthedisease.Theidentificationofnewtherapeutictargets,suchastheRIP1/RIP3/MLKLpathway,theangiopoietin-Tie2signalingpathway,andHIF-2α,provideshopeforthedevelopmentofeffectivetreatmentsforthisdisorder.However,furtherresearchisneededtodeterminethesafetyandefficacyofthesepotentialtherapiesinhumanpatientswithCCMAnotherareaofresearchthatholdspromiseforthetreatmentofCCMisgenetherapy.Recentstudieshaveshownthatmodifyingtheexpressionofspecificgenescanreducetheformationandgrowthofcavernomas.OnestudyusedCRISPR/Cas9geneeditingtodecreasetheexpressionoftheKrit1geneinmousemodelsofCCM,resultinginasignificantreductioninthenumberandsizeofcavernomas.AnotherstudyusedantisenseoligonucleotidestoreducetheexpressionofthePdcd10gene,whichalsoledtoareductionintheformationofcavernomasinmousemodels.ThesefindingssuggestthatgenetherapymayofferapotentialtreatmentforCCMbytargetingspecificgenesinvolvedinthediseaseprocess.

Inadditiontodevelopingnewtherapies,itisalsoimportanttoconsiderstrategiesforpreventingthedevelopmentofCCM.WhilethereiscurrentlynoknowncureforCCM,identifyingindividualswhoareatriskfordevelopingthedisorderandimplementingpreventativemeasurescouldhelptoreducetheoverallincidenceofthedisease.OneapproachcouldbetoscreenindividualswithafamilyhistoryofCCMusinggenetictestingandimagingstudies,andtoprovideearlyinterventionssuchasprophylacticsurgeryforthoseathighrisk.

Inconclusion,CCMisacomplexdisorderwithasignificantimpactonindividualsandfamilies.Whileprogresshasbeenmadeinunderstandingtheunderlyinggeneticsandpathologyofthedisease,effectivetreatmentsremainelusive.Continuedresearchintothemolec