Type B monoamine oxidase and neurotoxins.

The biochemical process underlying Parkinson's disease is dopamine cell death of the nigrostriatal system. The age-dependent cell death is now proposed to be elicited by the formation of free hydroxy radicals which are formed from hydrogen peroxide, a product of oxidation of dopamine by monoamine oxidase, especially type B. The potent neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, was found to induce cell death by an energy crisis or oxidative stress in dopamine neurons. Other endogenous mammalian neurotoxins, monoamine-derived 1,2,3,4-tetrahydroisoquinolines and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, have been proposed as factors accelerating dopamine cell death. N-methylated isoquinolines were found to be oxidized by monoamine oxidase, and hydroxy radicals were found to be produced by this reaction. In addition, by incubation with the N-methylated isoquinolines, ATP was depleted from a dopaminergic cell model, clonal rat pheochromocytoma PC12h cells. ATP depletion could be protected by pretreatment of the cells with monoamine oxidase inhibitors. These results suggest that oxidation of neurotoxic isoquinolines is directly involved in the oxidative stress to induce the cell death of dopamine neurons. On the other hand, 1-methyl-1,2,3,4-tetrahydroisoquinoline and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were found to inhibit the activity of monoamine oxidase, indicating that they may be neuroprotective agents in the brain. The involvement of monoamine oxidase is discussed in relation to the pathogenesis of Parkinson's disease.