Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity

Abstract

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.

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

“…Support for this hypothesis is provided by the observation that MPP + -related ATP depletion causes only an approximately 20% reduction in ATP levels in the striatum and midbrain, which is not likely to be a severe enough depletion of ATP to be the primary cause of DA neuron death (17,25). Further support for the oxidative stress-mediated mechanism of mitochondrial dysfunction by MPTP is evidence that transgenic mice overexpressing the antioxidant Cu/Zn-superoxide dismutase enzyme have attenuated MPTP-induced DA neuron loss (78). Conversely, mice deficient in CuZn-superoxide dismutase (Cu/Zn SOD) or glutathione peroxidase exhibit enhanced DA neurotoxicity in response to MPTP (122).…”

An increase in superoxide dismutase ameliorates oxygen-induced retinopathy in transgenic mice

“…In the nervous system of adult mice, these sources of stress include freezing, blunt trauma, ischaemia and reperfusion, as well as injection of N-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine. [18][19][20][21]36,37 Sources of oxidative stress outside the nervous system include streptozotoxin, alloxan, 38 and tumour necrosis factor. 39 Protection against hyperoxia-related pulmonary toxicity has been documented in the same transgenic mice strain as that used in our study.…”

“…11 Superoxide dismutase (SOD) is a ubiquitous water-soluble enzyme known to exert antioxidant activity due to its function as a specific scavenger of the O 2 À anion. Supplementation of SOD both in vitro 12,13 and in vivo, [14][15][16][17] as well as overexpression of SOD in transgenic mice, [18][19][20][21] can protect against hyperoxic damage. These findings prompted us to examine whether overexpression of SOD would reduce the retinal vaso-attenuation, obliteration, and neovascularization caused by hyperoxia in a wellcharacterized model of ROP in transgenic mice.…”

Estrogen and Brain Protection

“…Studies have demonstrated that superoxide dismutase is implicated in dopamine and Parkinson's disease. Mutant mice that over-expressed or lacked superoxide dismutase were more resistant to (Przedborski et al, 1992) or vulnerable to (Andreassen et al, 2001; dopamine neurotoxin than wild type mice, respectively. The expression of superoxide dismutase was upregulated in the substantia nigra following the dopamine neurotoxin insult, yet the loss of dopaminergic neurons still occurred (Tripanichkul et al, 2007).…”