title: AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease.
abstract: We have recently shown that intrastriatal injection of recombinant human erythropoietin (EPO) protects dopaminergic (DA) neurons in the substantia nigra (SN) from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of Parkinson's disease. However, systemic administration of EPO did not protect nigral DA neurons, suggesting that the blood-brain barrier limits the passage of EPO protein into the brain. In the present study, we used an adeno-associated viral (AAV) serotype 9 (AAV9) vector to deliver the human EPO gene into the brain of 6-OHDA-lesioned rats. We observed that expression of the human EPO gene was robust and stable in the striatum and the SN for up to 10 weeks. EPO-immunoreactive (IR) cells were widespread throughout the injected striatum, and EPO-IR neurons and fibers were also found in the ipsilateral SN. Enzyme-linked immunosorbent assay and western blot analyses exhibited dramatic levels of EPO protein in the injected striatum. As a result, nigral DA neurons were protected against 6-OHDA-induced toxicity. Amphetamine-induced rotational asymmetry and spontaneous forelimb use asymmetry were both attenuated. Interestingly, we also observed that intrastriatal injection of AAV9-EPO vectors led to increased numbers of red blood cells in peripheral blood. This highlights the importance of using an inducible gene delivery system for EPO gene delivery.
authors.affiliation: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Xue
authors.forename: B-F
authors.initials: BF
authors.lastname: Ma
authors.forename: L-R
authors.initials: LR
authors.lastname: Zhao
authors.forename: J B
authors.initials: JB
authors.lastname: Tatom
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.forename: L-X
authors.initials: LX
authors.lastname: Jiang
authors.forename: R L
authors.initials: RL
authors.lastname: Klein
authors.forename: W-M
authors.initials: WM
authors.lastname: Duan
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006892:Hydroxydopamines / Q000378:metabolism; D010300:Parkinson Disease / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013378:Substantia Nigra
chemical_list: D006892:Hydroxydopamines; D011994:Recombinant Proteins; D004921:Erythropoietin