Netrin-1對OGD損傷后皮層神經(jīng)元凋亡、突起生長和突觸形成的影響及機制研究摘要

缺血性腦卒中是導(dǎo)致殘疾和死亡的常見疾病。在腦缺血發(fā)生后，神經(jīng)元凋亡、突觸失調(diào)、神經(jīng)元突起受損等現(xiàn)象加重了腦損傷。Netrin-1是一種重要的神經(jīng)發(fā)育指導(dǎo)分子，它可以在神經(jīng)系統(tǒng)中促進神經(jīng)元突起、軸突導(dǎo)向和突觸形成等過程。此外，增強Netrin-1的表達可以減輕大腦缺血損傷。然而，Netrin-1在OGD（缺氧/低氧）后對皮層神經(jīng)元的影響及其機制仍不清楚。本研究通過OGD模型，探究了Netrin-1對OGD損傷后皮層神經(jīng)元凋亡、突起生長和突觸形成的影響及其作用機制。結(jié)果顯示，注射Netrin-1能夠減少OGD損傷后皮層神經(jīng)元的凋亡，促進神經(jīng)元突起的生長和突觸的形成。這些結(jié)果進一步證明了Netrin-1在腦缺血損傷后具有保護神經(jīng)元、促進神經(jīng)元修復(fù)的作用。我們的研究結(jié)果進一步闡明了Netrin-1的作用機制：Netrin-1通過AKT和ERK途徑促進神經(jīng)元生長和突觸的形成。綜上所述，這些結(jié)果表明Netrin-1能夠促進突觸形成和神經(jīng)元的生長，從而減輕OGD損傷對神經(jīng)元的損害。

關(guān)鍵詞：Netrin-1；OGD模型；神經(jīng)元凋亡；突觸形成；AKT和ERK途徑

Abstract

Ischemicstrokeisacommondiseasethatleadstodisabilityanddeath.Aftercerebralischemia,neuronalapoptosis,synapticimbalance,andimpairedneuronalprojectionsexacerbatebraindamage.Netrin-1isanessentialneurodevelopmentalguidancemoleculethatcanpromoteprocessessuchasneuriteoutgrowth,axonalguidance,andsynapticformationinthenervoussystem.Furthermore,increasingtheexpressionofNetrin-1canalleviatebrainischemicinjury.However,theeffectsofNetrin-1oncorticalneuronsafterOGD(oxygenandglucosedeprivation)anditsmechanismsarenotclear.Inthisstudy,weinvestigatedtheeffectsofNetrin-1oncorticalneuronapoptosis,neuriteoutgrowth,andsynapticformationafterOGDanditsmechanisms.OurresultsshowedthatinjectionofNetrin-1reducedcorticalneuronapoptosisandpromotedneuriteoutgrowthandsynapticformationafterOGD.TheseresultsfurtherdemonstratedthatNetrin-1hasaprotectiveeffectontheneuronsandcanpromoteneuronalrepairafterbrainischemicinjury.OurfindingsprovidefurtherinsightintothemechanismsofNetrin-1inpromotingneuronalgrowthandsynapticformationbyactivatingtheAKTandERKpathways.Inconclusion,thisstudyshowsthatNetrin-1canpromotesynapticformationandneuronalgrowth,therebymitigatingthedamagingeffectsofOGDinjurytoneurons.

Keywords:Netrin-1;OGDmodel;neuronalapoptosis;synapticformation;AKTandERKpathwaysNetrin-1isasecretedguidancecueproteinthatisknowntobeinvolvedinthedevelopmentofthenervoussystem.Inrecentyears,studieshaveshownthatNetrin-1alsoplaysaroleinthemaintenanceandrepairofthenervoussystem.OurstudyaimedtoinvestigatetheeffectsofNetrin-1onsynapticformationandneuronalgrowthinanoxygen-glucosedeprivation(OGD)modelofbrainischemicinjury.

WefoundthatNetrin-1treatmentsignificantlyincreasedsynapticdensityanddendriticlengthinculturedneuronssubjectedtoOGDinjury.Thiseffectwasaccompaniedbyadecreaseinneuronalapoptosis,suggestingthatNetrin-1mayprotectneuronsfromOGD-inducedcelldeath.Inaddition,wefoundthatNetrin-1treatmentupregulatedtheactivationofAKTandERK,twokeysignalingpathwaysinvolvedinneuronalgrowthandsurvival.

ThesefindingssuggestthatNetrin-1mayhavetherapeuticpotentialinthetreatmentofbrainischemicinjurybypromotingneuronalrepairandreducingneuronaldeath.FurtherstudiesareneededtoinvestigatetheexactmechanismsbywhichNetrin-1exertsitseffectsonneuronalgrowthandsurvival,andtodeterminetheoptimaldosingandadministrationstrategiesforNetrin-1inthecontextofbrainischemicinjury.Nevertheless,ourstudyprovidesvaluableinsightsintothepotentialtherapeuticapplicationsofNetrin-1inneurologicaldisordersInadditiontoitspotentialinthetreatmentofbrainischemicinjury,Netrin-1hasalsobeeninvestigatedinotherneurologicaldisorderssuchasAlzheimer'sdisease,Parkinson'sdisease,andspinalcordinjury.

Alzheimer'sdiseaseischaracterizedbyprogressivecognitiveimpairmentandmemoryloss,andiscausedbytheaccumulationofamyloidbetaplaquesandneurofibrillarytanglesinthebrain.Netrin-1hasbeenshowntohaveneuroprotectiveeffectsagainstamyloidbeta-inducedneurotoxicityinculturedneurons,andtoattenuatecognitivedeficitsinamousemodelofAlzheimer'sdisease(Liuetal.,2015;Wangetal.,2020).ThesefindingssuggestthatNetrin-1mayhavetherapeuticpotentialinthepreventionandtreatmentofAlzheimer'sdisease.

Parkinson'sdiseaseisaneurodegenerativedisordercharacterizedbythelossofdopaminergicneuronsinthesubstantianigra,leadingtomotorsymptomssuchastremors,rigidity,andbradykinesia.Netrin-1hasbeenshowntopromotethesurvivalanddifferentiationofdopaminergicneuronsinvitroandinvivo,andtoimprovemotorfunctioninamousemodelofParkinson'sdisease(Fengetal.,2019;Wangetal.,2018).TheseresultssuggestthatNetrin-1mayhavetherapeuticpotentialinthetreatmentofParkinson'sdiseasebypromotingdopaminergicneuronsurvivaland/orregeneration.

Spinalcordinjuryisadevastatingneurologicaldisorderthatoftenleadstoparalysisandlossofsensoryfunctionbelowthelevelofinjury.Netrin-1hasbeenshowntopromoteaxonalregenerationandfunctionalrecoveryinanimalmodelsofspinalcordinjury,possiblybypromotingthegrowthandguidanceofaxonsacrosstheinjurysite(Liuetal.,2018;Zhengetal.,2015).ThesefindingssuggestthatNetrin-1mayhavetherapeuticpotentialinthetreatmentofspinalcordinjurybypromotingaxonalregenerationandfunctionalrecovery.

Inconclusion,Netrin-1isapromisingtherapeutictargetforthetreatmentofneurologicaldisorders,includingbrainischemicinjury,Alzheimer'sdisease,Parkinson'sdisease,andspinalcordinjury.FurtherresearchisneededtofullyunderstandthemechanismsbywhichNetrin-1exertsitseffectsonneuronalgrowthandsurvival,andtooptimizeitsdosingandadministrationstrategiesforclinicaluse.Nevertheless,thepotentialtherapeuticapplicationsofNetrin-1inthesedevastatingneurologicaldisordersofferhopeforthedevelopmentofnewandeffectivetreatmentsinthefutureRecentresearchhasalsoexploredthepotentialofNetrin-1inpromotingtissuerepairandregenerationoutsideofthenervoussystem.StudieshaveinvestigatedtheuseofNetrin-1inpromotingwoundhealing,muscleregeneration,andbonerepair.

OnestudyfoundthatNetrin-1promoteswoundhealingbypromotingthemigrationofskincellsandenhancingtheformationofbloodvessels.AnotherstudyfoundthatNetrin-1promotesmuscleregenerationbyactivatingsatellitecells,whichareresponsibleforrepairingdamagedmuscletissue.

Similarly,researchhasshownthatNetrin-1promotesbonerepairbyenhancingtheformationofnewbonetissueandreducinginflammationinbonetissue.

Overall,thesestudiessuggestthatNetrin-1mayhaveimportantapplicationsinpromotingtissuerepairandregeneration,andmayoffernewtreatmentoptionsforawiderangeofinjuriesanddiseases.

Inconclusion,Netrin-1isahighlypromisingmoleculewithawiderangeofpotentialtherapeuticapplications.Itsuniqueroleinpromotingbothgrowthandguidanceofneurons,andinpromotingtissuerepairandregeneration,makesitahighlyattractivetargetforthedevelopmentofnewtreatmentsforawiderangeofneurologicalandmusculoskeletaldisorder