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Journal of Neuroscience, Vol 12, 1658-1667, Copyright © 1992 by Society for Neuroscience
Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity
S Przedborski, V Kostic, V Jackson-Lewis, AB Naini, S Simonetti, S Fahn, E Carlson, CJ Epstein and JL Cadet
Laboratory of Preclinical Neurosciences, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to
mammals causes damage to the nigrostriatal dopaminergic pathway similar to
that observed in Parkinson's disease. It has been suggested that the
mechanism by which MPTP kills dopamine (DA) neurons involves an energy
crisis due to the inhibition of mitochondrial complex I. In addition,
superoxide radicals (O2-), generated subsequent to the blockade of
mitochondrial complex I, may also be involved in MPTP- induced
neurotoxicity. Superoxide dismutase (SOD) is a scavenger enzyme that
protects cells from the hazard of O2- radicals. To evaluate further the
role of O2- radical in MPTP-induced toxicity, we tested the effects of MPTP
in transgenic mice with increased SOD activity. In nontransgenic
littermates with normal SOD activity, MPTP injection causes a marked
reduction in striatal levels of DA and its metabolites as well as in
striatal and nigral 3H-DA uptake; these findings are consistent with a loss
in dopaminergic neurons. In contrast, in transgenic mice with increased SOD
activity, MPTP injection does not cause any significant changes either in
levels of DA and metabolites or in 3H-DA uptake. We show that this lack of
toxicity is not due to a lower delivery of MPTP to the brain following its
intraperitoneal injection, to reduced brain biotransformation of MPTP to
N-methyl-4- phenylpyridinium ion (MPP+), to diminished striatal
mitochondrial monoamine oxidase B activity, to decreased synaptosomal
uptake of MPP+, to lower potency of MPP+ to inhibit the complex I of the
mitochondrial electron transport chain, or to faster brain elimination of
MPP+. These results suggest that increased SOD activity is, most likely,
the protective factor that confers resistance to transgenic mice against
MPTP-induced neurotoxicity. Thus, this study provides further evidence that
some of the deleterious effects of MPTP may be mediated by O2- radicals.
The similarity between the MPTP model and Parkinson's disease further
raises the possibility that oxy-radicals may play a significant role in the
etiology of this neurodegenerative disorder.
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