1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced complex I inhibition is reversed by disulfide reductant, dithiothreitol in mouse brain
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced complex I inhibition is reversed by disulfide reductant, dithiothreitol in mouse brain
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DOI：
10.1016/s0304-3940(00)01300-8
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发表时间：
2000-08-11
影响因子：
2.5
通讯作者：
Ravindranath, V
中科院分区：
文献类型：
--
作者：
Annepu, J;Ravindranath, V
1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)通过其代谢产物MPP+与复合体-1上的特定位点结合，抑制线粒体复合体-1，从而导致小鼠多巴胺能细胞丢失。由于Complex-1非常容易受到氧化应激的影响，我们研究了MPTP对Complex-1的抑制性质。在体外，MPTP和MPP+都抑制了小鼠脑片中的Complex-1活性，这种抑制作用可以被预先暴露于谷胱甘肽的脑片所消除。此外，被抑制的复合体-1活性在与二硫代还原剂二硫苏糖醇孵育后反弹。小鼠全身注射MPTP后，纹状体和中脑中的复合体-1受到抑制，而用二硫苏糖醇处理线粒体后，这种抑制作用被逆转。MPTP对复合体活性的抑制可能是由于复合体-1中的硫醇基团(S)氧化所致，而这种氧化作用可能被硫醇抗氧化剂逆转。(C)2000爱思唯尔爱尔兰科学有限公司。保留所有权利。
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes dopaminergic cell loss in mice by inhibiting mitochondrial complex-1 through its metabolite, MPP+, which binds to specific sites on complex-1. Since complex-1 is highly vulnerable to oxidative stress, we have examined the nature of inhibition of complex-1 by MPTP. Both MPTP and MPP+ inhibited complex-1 activity, in vitro, in mouse brain slices, which was abolished by prior exposure of brain slices to glutathione. Further, the inhibited complex-1 activity rebounded after incubation with disulfide reductant, dithiothreitol. Systemic administration of MPTP to mice resulted in inhibition of complex-1 in striatum and midbrain which was also reversed by treatment of mitochondria with dithiothreitol. Inhibition of complex activity by MPTP may be due to oxidation of thiol group(s) in complex-1, which may be reversed by thiol antioxidants. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.