Ethanol-induced neuronal apoptosis in vivo requires BAX in the developing mouse brain.
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-XL 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.
D000818:Animals; D020643:Anterior Thalamic Nuclei / Q000187:drug effects / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D045304:Cytochromes c / Q000032:analysis; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005838:Genotype; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D013049:Spectrin / Q000032:analysis; D013997:Time Factors; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013049:Spectrin; D000431:Ethanol; D045304:Cytochromes c; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases