期刊
CELL DEATH AND DIFFERENTIATION
卷 10, 期 10, 页码 1148-1155出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401277
关键词
alcohol; apoptosis; Bax knockout; caspase-3; neurons
资金
- NIA NIH HHS [AG 11355] Funding Source: Medline
- NICHD NIH HHS [HD 37100] Funding Source: Medline
- NIDA NIH HHS [DA 05072] Funding Source: Medline
- NINDS NIH HHS [NS35107] Funding Source: Medline
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.
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