Ethanol-induced neuronal apoptosis in vivo requires BAX in the developing mouse brain
Ethanol-induced neuronal apoptosis in vivo requires BAX in the developing mouse brain
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DOI：
10.1038/sj.cdd.4401277
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发表时间：
2003-10-01
影响因子：
12.4
通讯作者：
Olney, JW
中科院分区：
文献类型：
--
作者：
Young, C;Klocke, BJ;Olney, JW
单次乙醇中毒可引发幼年大鼠或小鼠脑内广泛的凋亡性神经变性。细胞死亡过程发生在乙醇给药后的6-16小时内，伴随着胱天蛋白酶-3酶激活的强烈显示，并符合细胞凋亡的超微结构标准。已经描述了两种凋亡途径（内在和外在），其中任何一种都可能导致caspase-3的激活。内源性途径由Bax和Bcl-X-L调节，并涉及作为导致半胱天冬酶-3激活的前因事件的线粒体功能障碍和细胞色素c的释放。在外源性途径中，caspase-8的活化是先于caspase-3活化的关键事件。在本研究中，乙醇给药后的幼年小鼠，我们发现没有变化，活化的caspase-8，这表明外源性途径不参与乙醇诱导的细胞凋亡。我们还发现乙醇在C57 BL/6野生型小鼠中引发了强烈的caspase-3激活和凋亡性神经变性，但在纯合子caspase-3缺陷小鼠中既不诱导这种现象。因此，乙醇诱导的神经细胞凋亡似乎是一种内在的途径介导的现象，涉及线粒体膜的破坏和细胞色素c的释放作为早期事件，导致caspase-3激活。
A single episode of ethanol intoxication triggers widespread apoptotic neurodegeneration in the infant rat or mouse brain. The cell death process occurs over a 6-16 h period following ethanol administration, is accompanied by a robust display of caspase-3 enzyme activation, and meets ultrastructural criteria for apoptosis. Two apoptotic pathways (intrinsic and extrinsic) have been described, either of which may culminate in the activation of caspase-3. The intrinsic pathway is regulated by Bax and Bcl-X-L and involves Bax-induced mitochondrial dysfunction and release of cytochrome c as antecedent events leading to caspase-3 activation. Activation of caspase-8 is a key event preceding caspase-3 activation in the extrinsic pathway. In the present study, following ethanol administration to infant mice, we found no change in activated caspase-8, which suggests that the extrinsic pathway is not involved in ethanol-induced apoptosis. We also found that ethanol triggers robust caspase-3 activation and apoptotic neurodegeneration in C57BL/6 wildtype mice, but induces neither phenomenon in homozygous Bax-deficient mice. Therefore, it appears that ethanol-induced neuroapoptosis is an intrinsic pathway-mediated phenomenon involving Bax-induced disruption of mitochondrial membranes and cytochrome c release as early events leading to caspase-3 activation.