The endogenous
neurotoxin 1-methyl-6,7-dihydroxy-1,2,3, 4-tetrahydroisoquinoline (
salsolinol), which is structurally similar to
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP), has been reported to inhibit mitochondrial complex I (
NADH-Q
reductase) activity as does the
MPTP metabolite
1-methyl-4-phenylpyridinium ion (MPP(+)). However, the mechanism of
salsolinol leading to neuronal cell death is still unknown. Thus, we correlated indices of cellular energy production and cell viability in human dopaminergic
neuroblastoma SH-SY5Y cells after exposure to
salsolinol and compared these results with data obtained with MPP(+). Both toxins induce time and dose-dependent decrease in cell survival with IC(50) values of 34 microM and 94 microM after 72 h for
salsolinol and MPP(+), respectively. Furthermore,
salsolinol and MPP(+) produce a decrease of intracellular net
ATP content with IC(50) values of 62 microM and 66 microM after 48 h, respectively. In contrast to MPP(+),
salsolinol does not induce an increase of intracellular net
NADH content. In addition, enhancing glycolysis by adding
D-glucose to the culture medium protects the cells against MPP(+) but not
salsolinol induced cellular
ATP depletion and cytotoxicity. 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.