Biochemical mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Could oxidative stress be involved in the brain?

The parkinsonogenic neurotoxin, 1-methyl-4phenyl-l ,2,3,6-tetrahydropyridine (MPTP), is known to be a mitochondrial toxin in oitro. However, MPTP and a toxic metabolite, 1-methyl-4-phenylpyridine (MPP+), are also known to produce oxidative stress in the lung just like the MPP ÷ structural congener, paraquat [1,2]. MPP ÷ stimulates the release of glutathione disulfide into the plasma, probably after release from lung cells. This rise in glutathione disulfide levels is a fairly specific indicator of oxidative stress induction and of the action of glutathione peroxidase to detoxify hydrogen peroxide formed during oxidative stress [3, 4]. In addition, both MPTP and MPP ÷ are much more toxic to selenium-deficient mice than normal mice [1, 2], which indicates the importance of the selenoenzyme, glutathione peroxidase, in the pulmonary toxicity of these compounds. This evidence is very strong support for the induction of oxidative stress by MPTP in the lung. A more detailed discussion of the biochemistry of oxidative stress is provided below. The question that will be asked here is what is the importance of oxidative stress in the brain during MPTP-induced toxicity. Oxidative stress would be induced by the redox cycling of MPP ÷ which involves the one electron reduction of MPP ÷ by cytochrome P450 reductase, which is present in dopaminergic neurons and their projections in the striatum [5], or some other reductive process. The MPP radical formed must be stable enough to reduce oxygen which produces superoxide radical anion and leads to the production of active oxygen species which are toxic to cells. The selective toxicity of MPP ÷ to dopaminergic neurons is due to its specific uptake by the dopamine uptake system following its release from astrocytes [6].