R(-)-deprenyl potentiates dopamine-induced cytotoxicity toward catecholaminergic neuroblastoma SH-SY5Y cells.
Autoxidation of dopamine or L-DOPA (3,4-dihydroxyphenylalanine) generates reactive oxygen species (ROS), i.e., hydrogen peroxide, superoxide, and hydroxyl radical, which are potentially cytotoxic. Increased formation of ROS has been proposed to be involved in the pathogenesis of many human diseases, including Parkinson's disease. Several reports suggest that R(-)-deprenyl (an MAO-B inhibitor and anti-Parkinsonian drug) may directly or indirectly exert antioxidant effects and thus protect neurons. We have assessed the toxic effects of dopamine and L-DOPA toward catecholaminergic neuroblastoma SH-SY5Y cells and whether R(-)-deprenyl and several structurally related compounds possess antioxidant effects in this system. The results show that both dopamine and L-DOPA are quite cytotoxic toward SH-SY5Y cells. R(-)-deprenyl rather than reducing this dopamine-induced toxicity actually enhances it. Structural analogues of R(-)-deprenyl, such as 4-methyldeprenyl, (-)-methylamphetamine, and clorgyline, exhibited similar effects. Some different MAO-B inhibitors, namely, the aliphatic N-methylpropargylamines, e.g., (+/-)-M-2-PP [N-(2-pentyl)-N-methylpropargylamine] and N-[2-hexyl]-N-methylpropargylamine, which can also protect and rescue neurons in several in vivo and in vitro models, did not exacerbate the cytotoxicity of dopamine. Neither R(-)-deprenyl nor (+/-)-M-2-PP affected the L-DOPA-induced cytotoxicity toward SH-SY5Y cells.
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Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
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D000975:Antioxidants / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology / Q000633:toxicity*; D004357:Drug Synergism; D006801:Humans; D007980:Levodopa / Q000494:pharmacology / Q000633:toxicity; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D012642:Selegiline / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000975:Antioxidants; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011437:Propylamines; D017382:Reactive Oxygen Species; C082737:N-methyl-N-(2-pentyl)propargylamine; C094098:N-2-hexyl-N-methylpropargylamine; D012642:Selegiline; D007980:Levodopa; D010293:Pargyline; D004298:Dopamine