MTTP, L-deprenyl and Parkinson's disease : pharmacological implications of oxidative stress

Excessive free radical formation or antioxidant enzyme deficiency can result in oxidative stress, a mechanism proposed in the toxicity of MPTP and in the etiology of Parkinson's disease (PD). To be effective as a toxin, MPTP must be metabolized by monoamine oxidase-B (MAO-B) to form MPP$ sp+.$ The latter compound leads to the degeneration of the dopaminergic cell bodies of the substantia nigra (SN) and striatal dopamine (DA) depletion that are reminescent of PD. The toxic effects of MPP$ sp+$ are related to the inhibition of NADH dehydrogenase activity in the mitochondrial respiratory chain. This event leads to the rapid depletion of ATP synthesis and loss of membrane potential to further enhance free radical formations. Similar respiratory deficits are reported in PD. The major antioxidant enzymes in the CNS are superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT). SOD catalyses the dismutation of superoxide (O$ sb2 sp{ cdot}$) radical into H$ sb2$O$ sb2$, while GSH-PX and CAT convert H$ sb2$O$ sb2$ to H$ sb2$O. Lipid peroxidation and SOD activity are increased in PD brains, whereas CAT and GSH-PX remain unchanged or reduced. This observation is suggestive of a deficiency in dealing with excessive H$ sb2$O$ sb2$ formation which exacerbates iron-catalysed free radical generations. To date however, it is unclear if the alteration in SOD activity observed in PD is sufficient to enhance free radical formation and, consequently, to increase lipid peroxidation. We were able to demonstrate that, despite marked alterations in SOD and CAT activities in the SN and striatum of MPTP-treated mice, lipid peroxidation remained unaffected. These results suggest that factors other than antioxidant enzymes play a pivotal role in the modulation of peroxidative damage to lipids as observed in PD. Surprisingly, L-deprenyl, a potent MAO-B inhibitor known to protect dopaminergic neurons against the deleterious effects of MPTP by blocking MPP$ sp+$ formation