title: Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease.
abstract: Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or beta-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase (TH)-positive DA fibers in the striatum and the number of TH-positive or cholera toxin subunit B (CTB, neuronal tracer)-labeled neurons in the SN were significantly greater in the AAV-GDNFflag group than in the AAV-LacZ group. Dopamine levels and those of its metabolites in the striatum were remarkably higher in the AAV-GDNFflag group compared with the control group. Consistent with anatomical and biochemical changes, significant behavioral recovery was observed from 4-20 weeks following AAV-GDNFflag injection. These data indicate that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD.
authors.affiliation: Department of Neurology, Jichi Medical School, Japan.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: K
authors.initials: K
authors.lastname: Ikeguchi
authors.forename: K
authors.initials: K
authors.lastname: Fujimoto
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: H
authors.initials: H
authors.lastname: Mizukami
authors.forename: Y
authors.initials: Y
authors.lastname: Hanazono
authors.forename: A
authors.initials: A
authors.lastname: Kume
authors.forename: F
authors.initials: F
authors.lastname: Urano
authors.forename: H
authors.initials: H
authors.lastname: Ichinose
authors.forename: T
authors.initials: T
authors.lastname: Nagatsu
authors.forename: I
authors.initials: I
authors.lastname: Nakano
authors.forename: K
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007267:Injections; D008297:Male; D023421:Models, Animal; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism*; D013997:Time Factors
chemical_list: C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016627:Oxidopamine; D004298:Dopamine