Protection and potentiation of MPTP-induced toxicity by cytochrome P-450 inhibitors and inducer: in vitro studies with brain slices.
Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes loss of dopaminergic neurons in humans, primates and mice. Exposure of sagittal slices of mouse brain to MPTP (100 pM) caused inhibition of mitochondrial NADH-dehydrogenase activity. Leakage of lactate dehydrogenase from the slice into the medium was observed following incubation of slices with 1 nM MPTP. Neurotoxicity induced by MPTP was prevented by prior exposure of the slices to the dopamine uptake inhibitor GBR 12935. Deprenyl and pargyline (inhibitors of monoamine oxidase), also protected the slices from MPTP-induced toxicity. However, both pargyline and deprenyl also inhibited cytochrome P-450 mediated aminopyrine N-demethylase activity in brain slices. Pargyline, when administered in vivo to mice, decreased brain cytochrome P-450 levels significantly. Other cytochrome P-450 inhibitors, namely, piperonyl butoxide and SKF 525A were found to offer protection against MPTP induced neurotoxicity in slices without affecting monoamine oxidase activity. MPTP toxicity was potentiated significantly in brain slices prepared from mice pretreated with phenobarbital, an inducer of cytochrome P-450. The present study suggests the possible involvement of cytochrome P-450 in MPTP-induced neurotoxicity, in vitro, in brain slices.
Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
K S
KS
Pai
V
V
Ravindranath
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010293:Pargyline / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D010879:Piperazines; D012642:Selegiline; D003577:Cytochrome P-450 Enzyme System; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011335:Proadifen; D006899:Mixed Function Oxygenases; D007770:L-Lactate Dehydrogenase; D009251:NADPH-Ferrihemoprotein Reductase; D010882:Piperonyl Butoxide; D010634:Phenobarbital