Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity.
Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and subhuman primates, but not in rats and many other laboratory animals; mice are intermediate in their susceptibility. Since MPTP causes selective dopaminergic neurotoxicity when infused directly into rat substantia nigra, we hypothesized that systemic MPTP may be metabolized by monoamine oxidase and/or other enzymes in rat brain capillaries and possibly other peripheral organs and thus prevented from reaching its neuronal sites of toxicity. We tested this hypothesis by assessing monoamine oxidase in isolated cerebral microvessels of humans, rats, and mice by measuring the specific binding of [3H]pargyline, an irreversible monoamine oxidase inhibitor, and by estimating the rates of MPTP and benzylamine oxidation. [3H]Pargyline binding to rat cerebral microvessels was about 10-fold higher than to human or mouse microvessels. Also, MPTP oxidation by rat brain microvessels was about 30-fold greater than by human microvessels; mouse microvessels yielded intermediate values. These results may explain, at least in part, the marked species differences in susceptibility to systemic MPTP. They also suggest the potential importance of "enzyme barriers" at the blood-brain interface that can metabolize toxins not excluded by structural barriers, and may provide biological bases for developing therapeutic strategies for the prevention of MPTP-induced neurotoxicity and other neurotoxic conditions including, possibly, Parkinson disease.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002560:Cerebrovascular Circulation; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism*; D009498:Neurotoxins; D010293:Pargyline / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D051381:Rats
D009498:Neurotoxins; D011725:Pyridines; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase