Dopamine Neuron Stimulating Actions of a GDNF Propeptide 英文参考文献.docVIP

DopamineNeuronStimulatingActionsofaGDNF Propeptide LukeH.Bradley1,2*,JoshFuqua1,AprilRichardson1,JadwigaTurchan-Cholewo1,YiAi1,KristenA. Kelps1,JohnD.Glass3,XiuquanHe1,ZhimingZhang1,RichardGrondin1,O.MeaganLittrell1 ,Peter Huettl1,FrancoisPomerleau1,DonM.Gash1,GregA.Gerhardt1 1Department of Anatomy Neurobiology and the Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington,Kentucky,UnitedStatesofAmerica,2DepartmentofMolecularCellularBiochemistryandtheCenterofStructuralBiology,UniversityofKentuckyCollegeof Medicine,Lexington,Kentucky,UnitedStatesofAmerica,3Shoreham,NewYork,UnitedStatesofAmerica Abstract Background: Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson’s disease (PD) clinicaltrials.However,thedeliveryofneurotrophicfactorstothebrainisdifficultduetotheirlargesizeandpoorbio-distribution. Inaddition,developingmoreefficacioustrophicfactorsis hamperedbythedifficultyofsynthesis andstructural modification. Smallmoleculeswithneurotrophicactionsthatareeasytosynthesizeandmodifytoimprovebioavailabilityareneeded. MethodsandFindings:Herewepresenttheneurobiologicalactionsofdopamineneuronstimulatingpeptide-11(DNSP- 11),an11-merpeptidefromtheproGDNFdomain.Invitro,DNSP-11supportsthesurvivaloffetalmesencephalicneurons, increasing both the number of surviving cells and neuritic outgrowth. In MN9D cells, DNSP-11 protects against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced cell death, significantly decreasing TUNEL-positive cells andlevelsofcaspase-3activity.Invivo,asingleinjectionofDNSP-11intothenormaladultratsubstantianigraistakenup rapidly into neurons and increases resting levels of dopamine and its metabolites for up to 28 days. Of particular note, DNSP-11 significantly improves apomorphine-induced rotational behavior, and