EphA4 Blockers Promote Axonal Regeneration and Functional Recovery Following Spinal Cord Injury in Mice 英文参考文献.docVIP

EphA4BlockersPromoteAxonalRegenerationand FunctionalRecoveryFollowingSpinalCordInjuryinMice YonaGoldshmit1.¤,MarkD.Spanevello2,3.,SophieTajouri3,LiLi3,FionaRogers3,MartinPearse5 ,Mary Galea6,PerryF.Bartlett3*,AndrewW.Boyd2,4*,AnnM.Turnley1* 1Centre for Neuroscience, The University of Melbourne, Parkville, Victoria, Australia, 2Queensland Institute of Medical Research, Herston, Queensland, Australia, 3Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia, 4Department of Medicine, The University of Queensland, Brisbane, Queensland,Australia,5CSLLimited,Parkville,Victoria,Australia,6PhysiotherapyDepartment,TheUniversityofMelbourne,Parkville,Victoria,Australia Abstract Upregulation andactivation ofdevelopmental axonguidance molecules,such as semaphorins andmembers of the Eph receptortyrosinekinasefamilyandtheirligands,theephrins,playaroleintheinhibitionofaxonalregenerationfollowing injury to the central nervous system. Previously we have demonstrated in a knockout model that axonal regeneration followingspinalcordinjuryispromotedintheabsenceoftheaxonguidanceproteinEphA4.AntagonismofEphA4was thereforeproposedasapotentialtherapytopromoterecoveryfromspinalcordinjury.Tofurtherassessthispotential,two solublerecombinantblockersofEphA4,unclusteredephrin-A5-FcandEphA4-Fc,wereexaminedfortheirabilitytopromote axonal regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial axonal regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocyticgliosis,indicatingthatmuchoftheeffectoftheblockersmaybeduetopromotionofaxongrowth.Thesestudies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatmentofspinalcordinjuryandmayhavebroaderpotentialforthetreatmentofothe