1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is toxic to dopaminergic neuroblastoma SH-SY5Y cells via impairment of cellular energy metabolism

The endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino line (salsolinol), which is structurally similar to 1-methyl-4-phenyl-1,2,3 ,6-tetrahydropyridine (MPTP), has been reported to inhibit mitochondrial co mplex I(NADH-Q reductase) activity as does the MPTP metabolite 1-methyl-3-p henylpyridinium ion (MPP+). However, the mechanism of salsolinol leading to neuronal cell death is still unknown. Thus, we correlated indices of cellu lar energy production and cell viability in human dopaminergic neuroblastom a SH-SY5Y cells after exposure to salsolinol and compared these results wit h data obtained with MPP+. Both toxins induce time and dose-dependent decre ase in cell survival with IC50 values of 34 mu M and 94 mu M after 72 h for salsolinol and MPP+, respectively. Furthermore, salsolinol and MPP+ produc e a decrease of intracellular net ATP content with IC50 values of 62 mu M a nd 66 mu M after 48 h, respectively. In contrast to MPP+, salsolinol does n ot induce an increase of intracellular net NADH content. Ln addition, enhan cing glycolysis by adding D-glucose to the culture medium protects the cell s against MPP+ but not salsolinol induced cellular ATP depletion and cytoto xicity. These results suggest that cell death induced by salsolinol is due to impairment of cellular energy supply, caused in particular by inhibition of mitochondrial complex II (succinate-Q reductase), but not complex I. (C ) 2000 Published by Elsevier Science B.V. All rights reserved.