MITOCHONDRIAL AND METABOLIC TOXICITY OF 1-METHYL-4-(2'-METHYLPHENYL)-1,2,3,6-TETRAHYDROPYRIDINE

  • 1 September 1987
    • journal article
    • research article
    • Vol. 242  (3) , 858-863
Abstract
In previous studies and in the accompanying paper, 1-methyl-4-(2''-methylphenyl)-1,2,3,6,-tetrahydropyridine (2''CH3-MPTP) was found to be more potent than MPTP in producing dopaminergic neurotoxicity in mice. One purpose of the present study was to determine whether 1-methyl-4-(2''-methyphenyl)pyridinium (2''CH3-MPTP+), the primary oxidation product of 2''CH3-MPTP both in vivo and in vitro, inhibits mitochondrial respiration as does 1-methyl-4-phenylpyridinium (MPP+), the primary oxidation product of MPTP. Another aim was to determine whether treatments which modify MPTP- and 2''CH3-MPTP-induced neurotoxicity in vivo also cause parallel changes in the metabolic toxicity of these compounds. It was found that 2''CH3-MPTP+, like MPP+, inhibited the oxidation of NAD(H)-linked substrates by isolated brain mitochondria in a concentration- and time-dependent manner, whereas succinate oxidation was not affected. Thus, the effect was on Complex I in the electron transport chain. Furthermore, 2''CH3-MPP+, like MPP+, enhanced lactate formation by neostriatal tissues slices as would be expected if Complex I respiration were inhibited. MPP+ was slightly more potent than 2''CH3-MPP+ in both of these studies. However, 2''CH3-MPTP was several-fold more potent than MPTP in increasing lactate accumulation by the neostriatal slices. This difference in potency correlated with the differing capacities of 2''CH3-MPTP and MPTP to be oxidized by monoamine oxidase (MAO). When neostriatrial slices were prepared from mice pretreated with selective doses of MAO-B inhibitors, MPTP- but not 2''CH3-MPTP-induced lactate formation was prevented completely, correlating well with the observation that selective doses of MAO-B inhibitors protect against MPTP- but not 2''CH3-MPTP-induced neurotoxicity in vivo. These findings indicate that both MPTP and 2''CH3-MPTP produce metabolic disturbances in neostriatal tissue slices consistent with the inhibition of mitochondrial respiration by the corresponding pyridinium ions formed as a result of the oxidation of MPTP and 2''CH3-MPTP by MAO.

This publication has 1 reference indexed in Scilit: