Toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.
The conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to its toxic 1-methyl-4-phenylpyridinium (MPP+) metabolite catalyzed by monoamine oxidase (MAO) type B is likely to occur within glial cells in the central nervous system. In this study, primary cultures of mouse astrocytes were used to assess the biochemical and toxic consequences of exposure to MPTP. MPTP caused a concentration-dependent loss of cell viability. This effect was probably due to the intracellular generation of MPP+, because cytotoxicity was prevented by preincubation of astrocytes in the presence of MAO inhibitors. After addition of 250 microM MPTP, loss of cell viability was preceded by an increased rate of glucose utilization and lactate accumulation, and by depletion of ATP. The ratio between the rates of lactate production (0.37 mM/hr) and glucose consumption (0.2 mM/hr) was 1.85, indicating that most of the glucose present in the medium was stoichiometrically converted to lactate via glycolysis. A remarkable correlation was found between ATP depletion and cytotoxicity caused by MPTP, and, when astrocytes were incubated in glucose-free medium, both ATP depletion and loss of viability occurred more rapidly. Finally, even after exposure for several days, astrocyte death could be prevented by washing MPTP from the incubation medium, suggesting that MPP(+)-induced mitochondrial damage may be reversible. We conclude that prolonged exposure of astrocytes to MPTP may result in loss of viability via the MAO-dependent generation of MPP+ and the ability of this toxic metabolite to impair mitochondrial function.(ABSTRACT TRUNCATED AT 250 WORDS)
Di Monte
D A
DA
California Institute for Medical Research, San Jose.
Wu
E Y
EY
Delanney
L E
LE
Irwin
I
I
Langston
J W
JW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects; D020267:MPTP Poisoning; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology
D008996:Monoamine Oxidase Inhibitors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium