Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline

• Published in: Life sciences (1973) 2007-07, Vol.81 (6), p.458-467
• Main Authors: Ogunrombi, Modupe O., Malan, Sarel F., Terre'Blanche, Gisella, Castagnoli, Kay, Castagnoli, Neal, Bergh, Jacobus J., Petzer, Jacobus P.
• Format: Article
• Language: English
• Subjects: 1-Methyl-3-phenyl-3-pyrroline; 1-Methyl-3-phenylpyrrole; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - analogs & derivatives; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - metabolism; Animals; Biotransformation; Brain - metabolism; Cattle; Dopamine; Dopamine - metabolism; Dopamine Agents - metabolism; In Vitro Techniques; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase - metabolism; Monoamine oxidase B; MPTP; MPTP Poisoning - metabolism; MPTP Poisoning - pathology; Neostriatum - drug effects; Neostriatum - metabolism; Neurotoxicity; Papio; Striata
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2007.06.014

The neurotoxic properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are dependent on its metabolic activation in a reaction catalyzed by centrally located monoamine oxidase B (MAO-B). This reaction ultimately leads to the permanently charged 1-methyl-4-phenylpyridinium species MPP +, a 4-electron oxidation product of MPTP and a potent mitochondrial toxin. The corresponding 5-membered analogue, 1-methyl-3-phenyl-3-pyrroline, is also a selective MAO-B substrate. Unlike MPTP, the MAO-B-catalyzed oxidation of 1-methyl-3-phenyl-3-pyrroline is a 2-electron process that leads to the neutral 1-methyl-3-phenylpyrrole. MPP + is thought to exert its toxic effects only after accumulating in the mitochondria, a process driven by the transmembrane electrochemical gradient. Since this energy-dependent accumulation of MPP + relies upon its permanent charge, 1-methyl-3-phenyl-3-pyrrolines and their pyrrolyl oxidation products should not be neurotoxic. We have tested this hypothesis by examining the neurotoxic potential of 1-methyl-3-phenyl-3-pyrroline and 1-methyl-3-(4-chlorophenyl)-3-pyrroline in the C57BL/6 mouse model. These pyrrolines did not deplete striatal dopamine while analogous treatment with MPTP resulted in 65–73% depletion. Kinetic studies revealed that both 1-methyl-3-phenyl-3-pyrroline and its pyrrolyl oxidation product were present in the brain in relatively high concentrations. Unlike MPP +, however, 1-methyl-3-phenylpyrrole was cleared from the brain quickly. These results suggest that the brain MAO-B-catalyzed oxidation of xenobiotic amines is not, in itself, sufficient to account for the neurodegenerative properties of a compound like MPTP. The rapid clearance of 1-methyl-3-phenylpyrroles from the brain may contribute to their lack of neurotoxicity.