Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors

Abstract

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes degeneration of the dopaminergic nigrostriatal pathway in several animal species, including humans^1,2, monkeys^3,4 and mice^5–7. Changes observed after MPTP administration include marked decrements in the neostriatal content of dopamine and its major metabolites, dihydroxyphenylacetic acid and homovanillic acid, and a greatly diminished capacity of neostriatal synaptosomes to take up ³H-dopamine^5,6. In contrast, there is no pronounced loss of serotonin in the neostriatum or of dopamine and its metabolites in other brain areas in MPTP-treated animals. The oxidative metabolism of MPTP to 1-methyl-4-phenyl pyridine, a positively charged species, has been suggested as a critical feature in the neurotoxic process⁸. Moreover, in rat brain preparations, the monoamine oxidase (MAO) inhibitor pargyline and the specific MAO-B inhibitor deprenil can prevent the formation of 1-methyl-4-phenyl-pyridine from MPTP, while the specific MAO-A inhibitor clorgyline has no such effect⁹, suggesting that MAO, and specifically MAO-B, is responsible for the oxidative metabolism of MPTP. We now report that pargyline, nialamide and tranylcypromine, which inhibit both MAO-A and MAO-B, when administered to mice before MPTP, protect against MPTP-induced dopaminergic neurotoxicity. Deprenil is also protective, but clorgyline is not. Our data are consistent with the premise that MAO-B has a crucial role in MPTP-induced degeneration of the nigrostriatal dopaminergic neuronal pathway.