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1‐methyl‐4‐phenylpyridinium neurotoxicity is attenuated by adenoviral gene transfer of human Cu/Zn superoxide dismutase
Author(s) -
Barkats Martine,
Horellou Philippe,
Colin Philippe,
Millecamps Stéphanie,
FauconBiguet Nicole,
Mallet Jacques
Publication year - 2005
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20696
Subject(s) - neuroprotection , substantia nigra , sod1 , superoxide dismutase , chemistry , oxidative stress , dopaminergic , tyrosine hydroxylase , mptp , neurotoxicity , striatum , medicine , microbiology and biotechnology , endocrinology , pharmacology , dopamine , biochemistry , biology , toxicity , organic chemistry
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 β‐galactosidase (Ad‐βgal) 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‐βgal 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. © 2005 Wiley‐Liss, Inc.