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Studies on the Neurotoxicity of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine: Inhibition of NAD‐Linked Substrate Oxidation by Its Metabolite, 1‐Methyl‐4‐Phenylpyridinium
Author(s) -
Vyas Ivy,
Heikkila Richard E.,
Nicklas William J.
Publication year - 1986
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1986.tb01768.x
Subject(s) - metabolite , nad+ kinase , neurotoxicity , chemistry , substrate (aquarium) , stereochemistry , medicinal chemistry , biochemistry , enzyme , toxicity , biology , organic chemistry , ecology
The effects of the parkinsonism‐inducing neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and its 4‐electron oxidation product 1‐methyl‐4‐phenylpyridinium (MPP + ) were studied in isolated mitochondria and in mouse brain striatal slices. ADP‐stimulated oxidation of NAD‐linked substrates was inhibited in a time‐dependent manner by MPP + (0.1–0.5 m M ), but not MPTP, in mitochondria prepared from rat brain, mouse brain, or rat liver. Under identical conditions, succinate oxidation was relatively unaffected. In neostriatal slices prepared from the mouse, a species susceptible to the dopaminergic neurotoxicity of MPTP, incubation with either MPP + or MPTP caused metabolic changes consistent with inhibition of mitochondnial oxidation, i.e., an increase in the formation of lactate and accumulation of the amino acids glutamate and alanine with concomitant decreases in glutamine and aspartate levels. The changes resulting from incubation with MPTP were prevented by the monoamine oxidase inhibitor pargyline, which blocks formation of MPP + from MPTP. The results suggest that compromise of mitochondrial function and its metabolic sequelae within dopaminergic neurons could be an important factor in the neurotoxicity observed after MPTP administration.