Neuroprotective Activities of Palmitoylethanolamide in an Animal Model of Parkinsons Disease 英文参考文献.docVIP

NeuroprotectiveActivitiesofPalmitoylethanolamidein anAnimalModelofParkinson’sDisease EmanuelaEsposito1,DanielaImpellizzeri1,EmanuelaMazzon1,2,IrenePaterniti1,SalvatoreCuzzocrea1* 1Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy, 2IRCCS Centro Neurolesi ‘‘Bonino- Pulejo’’,Messina,Italy Abstract The biochemical and cellular changes that occur following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP)areremarkablysimilartothatseeninidiopathicParkinson’sdisease(PD).PDischaracterizedbythedegenerationof dopaminergic nigrostriatal neurons, which results in disabling motor disturbances. Activation of glial cells and the consequentneuroinflammatoryresponseisincreasinglyrecognizedasaprominentneuropathologicalfeatureofPD.There is currently no effective disease-modifying therapy. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD. Chronic treatment with palmitoylethanolamide (PEA, 10mg/kg, i.p.), initiated 24hr after MPTP injection (20mg/kg), protected against MPTP-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100b overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS-positivecellsinthesubstantianigra.Furthermore,chronicPEAreversedMPTP-associatedmotordeficits,asrevealed by the analysis of forepaw step width and percentage of faults. Genetic ablation of peroxisome proliferator activated receptor(PPAR)-ainPPAR-aKOmiceexacerbatedMPTPsystemictoxicity,whilePEA-inducedneuroprotectionseemedbe partiallyPPARa-dependent.TheeffectsofPEAonmoleculestypicallyinvolvedinapoptoticpathwayswerealsoanalyzed. OurresultsindicatethatPEAprotectsagainstMPTP-inducedneu