Molecular mechanim of cytotoxicity induced by dopamine and 6-hydroxydopamine

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To promote possible neuroprotective strategies for Parkinson's disease, the present study was conducted to clarify differencies in biochemical mechanisms among cytotoxicites of dopamine (DA), levedopa (L-DOPA) and 6-hydroxydopamine (6-OHDA).1. DNA fragmentation induced by iron + hydrogen peroxide was extremely acclererated by DA and L-DOPA.Co-existence of 6-OHDA and zinc produed DNA fragmentation, although zinc alone did not produce DNA fragmentation. Aluminium-induced DNA fragmentation was differntly inhibited by DA-related compounds, indicating that action mechanism of alununium may be differant from those of the other transition metals.2. Production of hydroxyl radicals induced by iron was accelerated by 6-OHDA, although that was not affected by DA or L-DO PA.High production of hydroxyl radicals induced by cupper was suppressed by all DA-related compounds.3. Lipid peroxidation induced by iron was slightly inhibited by DA, but not affected by L-DOPA nor 6-OHDA.On the other hand, copper-induced lipid pereoxidation was extremely inhibited by DA, L-DOPA and 6-OHDA.4. Transition metals, especially copper, showed cytotoxicity against DAeregic neuronal cell line (B65). Among DA-related compounds, 6-OHDA showed cytotoxicity against B65 cells.5. Transition metals and 6-OHDA strongly increased superoxide dismutase (SOD) activities in B65 cells, but L-DOPA increased slightly SOD activities in those cells. Although iron and copper decreased slightly glutathione (GSH) activities, DA and 6-OHDA increased strongly GSH levels in B56 cells.Thus, DA, L-DOPA and 6-OHDA showed different cytotoxicities based on different interactions with transition metals, free radicals and redox states. The present results are useful information for establishing the neuroprotective strategies for Parkinson's disease.