ABSTRACT1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MITP) is a potent dopaminergic neurotoxin that causes biochemical, pharmacological, and pathological deficits in experimental animals similar to those seen in human parkinsonian patients.AUl of the deficits can be prevented by treating mice with selective inhibitors of monoamine oxidase B (MAO-B), including deprenyl, prior to MPTP administration. We now report that the dopaminergic neurotoxicity of two potent MPTP analogs, namely the 2'-methyl and 2'-ethyl derivatives (2'-MeMPTP and 2'-EtMPTP), cannot be prevented by deprenyl pretreatment. However, the neurotoxicity of these two analogs can be prevented by pretreatment with a combination of deprenyl and the selective MAO-A inhibitor clorgyline at doses that are sufficient to almost completely inhibit both MAO-B and MAO-A activities. Moreover, the neurotoxicity of 2'-EtMPTP (but not of 2'-MeMPTP and MPTP) can be significantly attenuated by clorgyline alone. There was a parallel between the capacity ofthe MAO inhibitors to decrease the brain content ofthe pyridinium species after adm ration of the tetrahydropyridines and the capacity of the MAO inhibitors to protect against the neurotoxic action of the tetrahydropyridines. The data support the conclusion that both 2'-MeMPTP and 2'-EtMPTP are bioactivated to pyridinium species to a significant extent by MAO-A. Further, it appears that the formation of the pyridinium species plays an important role in the neurotoxic process.The inadvertent self-administration of 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by several young drug abusers resulted in a severe parkinsonian syndrome (1-3). Moreover, the administration of MPTP to nonhuman primates causes behavioral, biochemical, and pathological deficits very similar to those observed in patients with idiopathic Parkinson disease (4, 5). There are at least two necessary steps involved in the MPTP-induced destruction of nigrostriatal dopaminergic neurons. First, MPTP is oxidized by monoamine oxidase B (MAO-B) to the 1-methyl4phenyl-2,3-dihydropyridinium species (MPDP+), which is then transformed either spontaneously or enzymatically to the 1-methyl-4-phenylpyridinium species (MPP+), the primary metabolite of MPTP found in the brains of experimental animals (6-9). Second, MPP+ is actively transported into the dopaminergic neurons by the dopamine-uptake system (10, 11). The importance of these two steps is indicated by the observations that pretreatment of experimental animals with inhibitors of either or dopamine uptake (10,16,17) prevents MPTP-induced neurotoxicity.We recently found that a 2'-substituted analog of MPTP, 1-methyl4(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-MeMPTP) (18,19) was a more potent nigrostriatal dopaminergic neurotoxin than MPTP in mice. As with MPTP, pretreatment with inhibitors of dopamine uptake prevented 2'-MeMPTP-induced neurotoxicity (19). However, unlike the case with MPTP, pretreatment with low and selective doses of MAO-B inhibitors did not prevent 2'-MeMPTPinduced neurotoxic...