Molecular regulation of acute ethanol-induced neuron apoptosis

• Published in: Journal of neuropathology and experimental neurology 2005-06, Vol.64 (6), p.490-497
• Main Authors: NOWOSLAWSKI, Lisa, KLOCKE, Barbara J, ROTH, Kevin A
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Anticonvulsants - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; bcl-2-Associated X Protein; Biological and medical sciences; Blotting, Western - methods; Caspase 3; Caspases - deficiency; Caspases - metabolism; Cell Survival - drug effects; Cells, Cultured; Central Nervous System Depressants - toxicity; Cerebellum - cytology; Cycloheximide - pharmacology; Dactinomycin - pharmacology; Diazepam - pharmacology; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Drug toxicity and drugs side effects treatment; Ethanol - toxicity; Excitatory Amino Acid Antagonists - pharmacology; Gene Expression Regulation - drug effects; Human viral diseases; Immunohistochemistry - methods; In Situ Nick-End Labeling - methods; Infectious diseases; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurology; Neurons - drug effects; Pharmacology. Drug treatments; Protein Synthesis Inhibitors - pharmacology; Proto-Oncogene Proteins c-bcl-2 - deficiency; Time Factors; Toxicity: nervous system and muscle; Tumor Suppressor Protein p53 - deficiency; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/64.6.490

Ethanol is a potent neurotoxin particularly for the developing nervous system. Intrauterine exposure to ethanol during the last trimester of human gestation can produce a broad spectrum of neuropathologic consequences. This period of human brain development is roughly equivalent to the first week of rodent postnatal life and acute exposure of neonatal mice to ethanol produces massive neuronal apoptosis throughout the brain. We have previously demonstrated that ethanol-induced neuron apoptosis is critically dependent on expression of Bax, a proapoptotic member of the Bcl-2 family. To further define the molecular pathway regulating ethanol-induced neuron apoptosis, we analyzed the effects of acute ethanol exposure on cerebellar internal granule cell neurons both in vivo and in vitro. Ethanol produced extensive Bax-dependent caspase-3 activation and neuron apoptosis in the cerebellar internal granule cell layer, which was maximal at approximately 6 hours postadministration. This effect was recapitulated in vitro and required new gene transcription, protein translation, Bax expression, and caspase activation. Ethanol-induced neuron death was independent of p53 expression and was unaffected by deficiency in the proapoptotic Bcl-2 family members Bid or Bad. These studies indicate that ethanol activates an intrinsic apoptotic death program in neurons that is likely to contribute to the neuropathologic effects of human fetal alcohol exposure.