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'-methylphenyl)pyridinium (2'CH3-MPP+), 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-MPP+, 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 tissue slices as would be expected if Complex 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).(ABSTRACT TRUNCATED AT 250 WORDS)
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|