Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl.
Monoamine oxidase (MAO) type A and type B were measured using kynuramine, 3,4-dihydroxyphenylethylamine (dopamine, DA), and 5-hydroxytryptamine (5-HT, serotonin) in 20 brain areas. The highest activities were found in the striatum (caudate nucleus, putamen, globus pallidus, and substantia nigra), hypothalamus, and c-mammilare. The ratio of DA to 5-HT deamination varied in the different regions, being in favor of DA in the striatum. With kynuramine as the substrate IC50 values of a number of inhibitors indicated that l-deprenyl was far more potent an inhibitor of human brain MAO than clorgyline or harmaline. N-Desmethylpropargylindane hydrochloride (AGN 1135) was also shown to have MAO-B inhibitory selectivity similar to that of l-deprenyl. Brains obtained at autopsy from l-deprenyl-treated Parkinsonian patients showed that, whereas MAO-B was fully inhibited by the therapeutic doses of l-deprenyl, substantial MAO-A activity was still evident. These results are matched by the significant increases of DA noted in caudate nucleus, globus pallidus, putamen, and substantia nigra and the unaltered 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the same regions. These data indicate that the therapeutic actions of l-deprenyl may lie in its selective inhibition of MAO-B resulting in increased brain levels of DA formed from L-dihydroxyphenylacetic acid (L-DOPA).
P
P
Riederer
M B
MB
Youdim
D000368:Aged; D000588:Amines / Q000378:metabolism*; D001921:Brain / Q000201:enzymology*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D007735:Kynuramine / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology*; D010627:Phenethylamines / Q000627:therapeutic use*; D012642:Selegiline / Q000494:pharmacology / Q000627:therapeutic use*; D012701:Serotonin / Q000378:metabolism; D014018:Tissue Distribution; D014191:Tranylcypromine / Q000494:pharmacology
D000588:Amines; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; C031967:rasagiline; D012642:Selegiline; D012701:Serotonin; D007735:Kynuramine; D014191:Tranylcypromine; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D004298:Dopamine