Cytotoxicity of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines

The in vivo effects of dopamine-derived alkaloids, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, salsolinols, and their N-methylated derivatives on a dopaminergic cell model, clonal rat pheochromocytoma PC12h cells, were examined by culture in the presence of various concentrations of the agents. The effects were evaluated in comparison with those by 1,2,3,4-tetrahydroisoquinoline and its N-methylated derivatives. Among 1,2,3,4-tetrahydroisoquinolines, only N-methylisoquinolinium ion had cytotoxic effect on PC12h cells. In general, 6,7-dihydroxyisoquinolines had more potent cytotoxic effect than N-methylisoquinolinium ion, and they reduced protein amounts of PC12h cells at 100 microM and 1 mM concentration. The specific activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, decreased with these isoquinolines at concentrations lower than those required to reduce the protein amount. The toxicity of N-methylated derivatives seems to be more potent than non-methylated isoquinolines. Salsolinols were proved to be accumulated in the mitochondrial fraction of the cells after 3 days in culture. N-methyl-1,2,3,4-tetrahydroisoquinoline depleted ATP from PC12h cells and it was prevented by preincubation with an inhibitor of type-A monoamine oxidase, clorgyline. These results indicate that N-methylated and oxidized derivatives of dopamine-derived alkaloids may be potent dopaminergic neurotoxins similar to 1-methyl-4-phenylpyridinium ion in the human brain and may induce Parkinson's disease after long years of accumulation.