GSK3beta in ethanol neurotoxicity.
Alcohol consumption during pregnancy is a significant public health problem and may result in a wide range of adverse outcomes for the child. The developing central nervous system (CNS) is particularly susceptible to ethanol toxicity. Children with fetal alcohol spectrum disorders (FASD) have a variety of cognitive, behavioral, and neurological impairments. FASD currently represents the leading cause of mental retardation in North America ahead of Down syndrome and cerebral palsy. Ethanol exposure during development causes multiple abnormalities in the brain such as permanent loss of neurons, ectopic neurons, and alterations in synaptogenesis and myelinogenesis. These alcohol-induced structural alterations in the developing brain underlie many of the behavioral deficits observed in FASD. The cellular and molecular mechanisms of ethanol neurotoxicity, however, remain unclear. Ethanol elicits cellular stresses, including oxidative stress and endoplasmic reticulum stress. Glycogen synthase kinase 3beta (GSK3beta), a multifunctional serine/threonine kinase, responds to various cellular stresses. GSK3beta is particularly abundant in the developing CNS, and regulates diverse developmental events in the immature brain, such as neurogenesis and neuronal differentiation, migration, and survival. Available evidence indicates that the activity of GSK3beta in the CNS is affected by ethanol. GSK3beta inhibition provides protection against ethanol neurotoxicity, whereas high GSK3beta activity/expression sensitizes neuronal cells to ethanol-induced damages. It appears that GSK3beta is a converging signaling point that mediates some of ethanol's neurotoxic effects.
Luo
Jia
J
Department of Internal Medicine, University of Kentucky College of Medicine, 124C Combs Research Building, 800 Rose Street, Lexington, KY 40536, USA. jialuo888@uky.edu
D000818:Animals; D002492:Central Nervous System Depressants / Q000633:toxicity*; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000473:pathology
D002492:Central Nervous System Depressants; D000431:Ethanol; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3