Molecular regulation of acute ethanol-induced neuron apoptosis.
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.
Department of Pathology, Division of Neuropathology University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
Lisa
L
Nowoslawski
Barbara J
BJ
Klocke
Kevin A
KA
Roth
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000633:toxicity*; D002531:Cerebellum / Q000166:cytology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D051028:bcl-2-Associated X Protein
D000927:Anticonvulsants; C494827:Bax protein, mouse; D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003609:Dactinomycin; D000431:Ethanol; D016291:Dizocilpine Maleate; D003513:Cycloheximide; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003975:Diazepam