1-methyl-4-phenylpyridinium neurotoxicity is attenuated by adenoviral gene transfer of human Cu/Zn superoxide dismutase.
Oxidative stress has been suggested to be an important mediator of dopaminergic cell death in Parkinson's disease (PD). We investigated the neuroprotective potential of Cu/Zn superoxide dismutase (SOD1) overexpression in the rat substantia nigra (SN) following adenovirus-mediated gene transfer. Human dopaminergic SK-N-SH cells were transduced with adenoviral vectors expressing either human SOD1 (Ad-SOD1) or beta-galactosidase (Ad-betagal) before exposure to 1 mM of the 1-methyl-4-phenylpyridinium ion (MPP+). A strong neuroprotective effect of SOD1 gene transfer was observed in the SK-N-SH cells exposed to MPP+ compared with controls. Adult rats were then given unilateral injections of either Ad-SOD1 or Ad-betagal into the striatum, and MPP+ was administered 8 days later at the same location. Strong transgene expression was detected in the SN dopaminergic neurons, a consequence of retrograde axonal transport of the adenoviral particles. The amphetamine-induced rotational behavior of the rats was markedly lower in Ad-SOD1-injected rats than in control animals. Also, behavioral recovery significantly correlated with the number of tyrosine hydrolase-expressing neurons in the SN of the treated rats. These results are consistent with oxidative stress contributing to the MPP+ -induced neurodegenerative process. They also indicate that SOD1 gene transfer into the nigrostriatal system may be a potential neuroprotective strategy for treating PD.
Barkats
Martine
M
Laboratoire de Genetique Moleculaire de la Neurotransmission et des Processus Neurodegeneratifs (LGN), CNRS UMR 7091, Paris, France. barkats@genethon.fr
Horellou
Philippe
P
Colin
Philippe
P
Millecamps
Stéphanie
S
Faucon-Biguet
Nicole
N
Mallet
Jacques
J
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002452:Cell Count / Q000379:methods; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D009043:Motor Activity / Q000502:physiology; D009447:Neuroblastoma; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D051381:Rats; D045442:Rotarod Performance Test / Q000379:methods; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism* / Q000627:therapeutic use*; D013778:Tetrazolium Salts; D013844:Thiazoles; D019076:Transgenes / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D013778:Tetrazolium Salts; D013844:Thiazoles; D014446:Tyrosine 3-Monooxygenase; D013482:Superoxide Dismutase; C022616:thiazolyl blue; D015655:1-Methyl-4-phenylpyridinium