Site-Specific and Time-Dependent Activation of the Endocannabinoid System after Transection of Long-Range Projections 英文参考文献.docVIP

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Site-Specific and Time-Dependent Activation of the Endocannabinoid System after Transection of Long-Range Projections 英文参考文献.doc

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Site-SpecificandTime-DependentActivationofthe EndocannabinoidSystemafterTransectionofLong- RangeProjections SonjaKallendrusch1,2,ConstanceHobusch1,AngelaEhrlich1,SimoneZiebell3,NatsuoUeda4, GerdGeisslinger3,MarcoKoch1,FaramarzDehghani1* 1InstituteforAnatomy,LeipzigUniversity,Leipzig,Germany,2LipidSignalingForschungszentrum,Frankfurt,Germany,3InstituteforPharmacology,GoetheUniversity, Frankfurt,Germany,4DepartmentofBiochemistry,KagawaUniversity,SchoolofMedicine,Kagawa,Japan Abstract Background:Afterfocalneuronalinjurytheendocannabinioidsystembecomesactivatedandprotectsorharmsneurons dependingoncannabinoidderivatesandreceptorsubtypes.Endocannabinoids(eCBs)playacentralroleincontrollinglocal responsesandinfluencingneuralplasticityandsurvival.However,littleisknownaboutthefunctionalrelevanceofeCBsin long-rangeprojectiondamageasobservedinstrokeorspinalcordinjury(SCI). Methods:Inratorganotypicentorhino-hippocampalslicecultures(OHSC)asarelevantandsuitablemodelforinvestigating projectionfibersintheCNSweperformedperforantpathwaytransection(PPT)andsubsequentlyanalyzedthespatialand temporaldynamicsofeCBlevels.Thisapproachallowsproperdistinctionofresponsesinoriginatingneurons(entorhinal cortex),areasofdeafferentiation/anterogradeaxonaldegeneration(dentategyrus)andputativechangesinmoredistant butsynapticallyconnectedsubfields(cornuammonis(CA)1region). Results: Using LC-MS/MS, we measured a strong increase in arachidonoylethanolamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels in the denervation zone (dentate gyrus) 24hours post lesion (hpl), whereas entorhinal cortex and CA1 region exhibited little if any changes. NAPE-PLD, responsible for biosynthesis of eCBs, was increasedearly,whereasFAAH,acatabolizingenzyme,wasup-regulated48hpl. Conclusion: Neuronal damage as assessed by transection of long-range projections apparently provides a strong time- dependentandarea-confinedsignalfordenovosynthesisofeCB, presumablytorestrict neuronaldamage.Thepresen