HSV-mediated delivery of erythropoietin restores dopaminergic function in MPTP-treated mice.
To investigate the neuroprotective effects of erythropoietin (EPO) in a rodent model of Parkinson disease, we inoculated a nonreplicating herpes simplex virus-based vector expressing EPO (vector DHEPO) into the striatum of mice 1 week prior to, or 2 weeks after, the start of continual administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (4 mg/kg intraperitoneally, 5 of 7 days) for 6 weeks. Inoculation with DHEPO prior to MPTP intoxication preserved behavioral function measured by pellet retrieval and the histological markers of tyrosine hydroxylase-immunoreactive (TH-IR) neuronal cell bodies in the substantia nigra (SN) and TH-IR and dopamine transporter-immunoreactive (DAT-IR) terminals in striatum. Inoculation of DHEPO 2 weeks into a 6-week course of MPTP resulted in improvement of behavioral function and restoration of TH-IR cells in SN and TH- and DAT-IR in the striatum. The effects of vector-produced EPO were similar in magnitude to the effects of vector-mediated expression of glial-derived neurotrophic factor in the same model. These results demonstrate that vector-mediated EPO production may be used to reverse dopaminergic neurodegeneration in the face of continued toxic insult.
Puskovic
Veljko
V
Department of Neurology, University of Michigan Health System and VA Ann Arbor Healthcare System, Ann Arbor, MI 48109, USA.
Wolfe
Darren
D
Wechuck
James
J
Krisky
David
D
Collins
Jeff
J
Glorioso
Joseph C
JC
Fink
David J
DJ
Mata
Marina
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018139:Simplexvirus / Q000235:genetics*
D004921:Erythropoietin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine