Inhibition of dopamine biosynthesis by tetrahydropapaveroline

Tetrahydropapaveroline (THP) at 5-15 μM has been found to induce l-DOPA-induced oxidative apoptosis in PC12 cells. In this study, the inhibitory effects of THP on dopamine biosynthesis in PC12 cells and tyrosine hydroxylase (TH) activity in bovine adrenal were investigated. Treatment of PC12 cells with THP at 2.5-10 μM significantly decreased the intracellular dopamine content in a concentration-dependent manner (21.3% inhibition at THP 10 μM). The activity of TH was also inhibited by the treatment with THP at 2.5-10 μM (23.4% inhibition at 10 μM). In addition, THP had an inhibitory effect on bovine adrenal TH (IC50 value, 153.9 μM). THP exhibited uncompetitive inhibition on bovine adrenal TH with a substrate l-tyrosine with the Ki value with l-tyrosine of 0.30 mM. Treatment with l-DOPA at 20-50 μM increased the intracellular dopamine content in PC12 cells and the increase in dopamine content by l-DOPA was in part inhibited when l-DOPA (20 and 50 μM) was associated with THP at non-cytotoxic (5-10 μM) or cytotoxic (15 μM) concentration ranges. However, the reduction of dopamine content by THP (15 μM) or THP (15 μM) associated with l-DOPA (20 and 50 μM) in PC12 cells was inversed by the antioxidant N-acetyl-cysteine (0.1 mM). These results indicate that THP at 5-10 μM decreases the basal dopamine content and reduces the increased dopamine content induced by l-DOPA in part by the inhibition of TH activity, and that THP at 15 μM does by oxidative stress in PC12 cells.