Monoamine oxidase and the bioactivation of MPTP and related neurotoxins: relevance to DATATOP
The DATATOP study is a clinical trial in which deprenyl, a selective inhibitor of monoamine oxidase-B (MAO-B), is being given to newly diagnosed Parkinsonian patients in an attempt to halt the progression of their disorder. In part, this is being done because of the working hypothesis than an MPTP-like molecule may be the cause of Parkinsonism, and deprenyl is known to protect against MPTP-induced dopaminergic neurotoxicity in experimental animals. In the present study we point out that several analogs of MPTP are good substrates not only for MAO-B but also for MAO-A. In addition, we point out that with long-term administration to rodents, deprenyl loses its selectivity as an inhibitor of MAO-B and also inhibits MAO-A. We believe that these observations have relevance for the DATATOP study.
KeywordsGood Substrate Tyrosine Hydroxylase Activity MPTP Administration Dopaminergic Neurotoxicity Parkinson Study Group
Unable to display preview. Download preview PDF.
- Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80:4546–4550.PubMedCrossRefGoogle Scholar
- Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC (1985) Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett 62:389–394.PubMedCrossRefGoogle Scholar
- Hoppel CL, Grinblatt D, Kwok HC, Arora PK, Singh MP, Sayre LM, Greenblatt D (1987) Inhibition of mitochondrial respiration by analogs of 4-phenylpyridine and 1-methyl-4-phenylpyridinium cation (MPP+ ), the neurotoxic metabolite of MPTP. Biochem Biophys Res Commun 148:684–693.PubMedCrossRefGoogle Scholar
- Sundstrom E, Stromberg I, Tsutsumi T, Olson L, Jonsson G (1987) Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57BL/6 mice. Comparison with three other strains of mice. Brain Res 405:26–38.Google Scholar
- Youngster SK, Sonsalla PK, Sieber BA, Heikkila RE (1989a) Structure activity of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurotoxicity I. Evaluation of the biological activity of MPTP analogs. J Pharmacol Exp Ther 249:820–828.Google Scholar
- Youngster SK, Nicklas WJ, Heikkila RE (1989b) Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity II. Evaluation of the biological activity of the pyridinium metabolites formed from the monoamine oxidase-catalyzed oxidation of MPTP analogs. J Pharmacol Exp Ther 249:829–835.Google Scholar