Abstract
1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induces parkinsonisms in humans, monkeys, and some animals. MPTP is metabolized to 1-methyl-4-phenylpyridine (MPP+), which is a primary neurotoxin, by monoamine oxidase B. MPP+ destroys nigro-striatal dopaminergic neurons, but the mechanism of the neurotoxic effects of MPP+ is not known. In this study, the effects of MPP+ on O-2 generation by neutrophils was examined. Neutrophils possess several functional and antigenic similarities to glial cells. Therefore, the O-2 generating system of neutrophils might be useful in studying the mechanism of MPP+ neurotoxicity related to active oxygen species.
1) MPP+ did not affect myristic acid (MA), and elaidic acid stimulated O-2 generation and H2O2 generation by the glucose-glucose oxidase system, suggesting that MPP+ did not react with O-2 or H2O2 itself.
2) When fatty acid-activated neutrophils were treated with a neutral detergent, Renex 30, and then NADPH was added, the O-2 generation by these permeabilized cells was inhibited by MPP+.
3) Kinetic study revealed that MPP+ was a noncompetitive inhibitor of the NADPH oxidase in plasma membranes isolated from MA-activated pig neutrophils.
These results did not support the hypothesis that the action of MPP+ is related to acitve oxygen species. The results suggest that MPP+ does not penetrate through the plasma membrane, and interacts with the inner domain of NADPH oxidase in the neutrophil plasma membranes. MPP+ inhibits NADPH oxidase, a hydrophobic flavoprotein, such as monoamine oxidase, NADH dehydrogenase and a-ketoglutarate dehydrogenase.
