Dopamine- and L-beta-3,4-dihydroxyphenylalanine hydrochloride (L-Dopa)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells. Effects of oxidative stress and antioxidative factors.
Enhanced oxidative stress has been suggested to be involved in the degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease. The high turnover rate of dopamine and/or unsequestered dopamine may cause an increase of formation of hydrogen peroxide via either oxidative deamination of dopamine by monoamine oxidase or autoxidation. Hydrogen peroxide would be converted to more toxic hydroxyl free radicals. L-beta-3,4-Dihydroxyphenylalanine hydrochloride (L-DOPA), the most useful drug in the symptomatic treatment of Parkinson's disease, has been considered to possess deteriorating degenerative side-effects. The catecholaminergic neuroblastoma SH-SY5Y cells were chosen to investigate the cytotoxic effect of dopamine and L-DOPA. Both dopamine and L-DOPA were found to be cytotoxic towards SH-SY5Y cells. Such toxic effects were accompanied by an increase of oxidative stress in the cell cultures and could be reversed effectively by catalase and to a lesser extent by superoxide dismutase. The non-enzymatic antioxidants L-ascorbic acid, glutathione, N-acetyl-L-cysteine, but not (+)-alpha-tocopherol, also completely protected SH-SY5Y cells against the cytotoxic effects induced by dopamine and L-DOPA. Antioxidative factors, namely free radical scavengers (including N-tert-butyl-alpha-phenylnitrone, salicylic acid, and D-mannitol) and a strong iron chelator, deferoxamine, however, did not protect the SH-SY5Y cells against dopamine and L-DOPA. The generation of reactive oxygen species and the resulting enhanced oxidative stress was clearly involved in the dopamine- and L-DOPA-induced cytotoxic effects. Hydrogen peroxide played the most important role related to cytotoxicity of dopamine and L-DOPA.
Lai
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Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
Yu
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D001205:Ascorbic Acid / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004298:Dopamine / Q000633:toxicity*; D007980:Levodopa / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology
D014810:Vitamin E; D007980:Levodopa; D002374:Catalase; D013482:Superoxide Dismutase; D003676:Deferoxamine; D001205:Ascorbic Acid; D004298:Dopamine