Storch A, Kaftan A, Burkhardt K, Schwarz J
Department of Neurology, University of Ulm Medical School, Oberer Eselsberg 45, 89081, Ulm, Germany.
Brain Res. 2000 Feb 7;855(1):67-75. doi: 10.1016/s0006-8993(99)02272-6.
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.
内源性神经毒素1-甲基-6,7-二羟基-1,2,3,4-四氢异喹啉（salsolinol），其结构与1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）相似，据报道它与MPTP代谢物1-甲基-4-苯基吡啶离子（MPP(+)）一样能抑制线粒体复合物I（NADH-Q还原酶）的活性。然而，salsolinol导致神经元细胞死亡的机制仍不清楚。因此，我们将人多巴胺能神经母细胞瘤SH-SY5Y细胞暴露于salsolinol后，关联细胞能量产生指标和细胞活力，并将这些结果与用MPP(+)获得的数据进行比较。两种毒素均诱导细胞存活率呈时间和剂量依赖性下降，salsolinol和MPP(+)在72小时后的IC(50)值分别为34 microM和94 microM。此外，salsolinol和MPP(+)分别在48小时后使细胞内净ATP含量下降，IC(50)值分别为62 microM和66 microM。与MPP(+)不同，salsolinol不会诱导细胞内净NADH含量增加。另外，通过向培养基中添加D-葡萄糖增强糖酵解可保护细胞免受MPP(+)诱导的细胞ATP消耗和细胞毒性，但不能保护细胞免受salsolinol的影响。这些结果表明，salsolinol诱导的细胞死亡是由于细胞能量供应受损，特别是由线粒体复合物II（琥珀酸-Q还原酶）而非复合物I的抑制引起的。
