Vitamin E amelioration of ethanol neurotoxicity involves modulation of apoptotis-related protein levels in neonatal rat cerebellar granule cells.

Developmental ethanol exposure leads to a variety of abnormalities in the central nervous system (CNS). Mechanisms proposed as underlying these effects include alterations of protective antioxidant support, increased generation of harmful free radicals, and altered expression of apoptosis-related proteins. In prior studies, exogenous antioxidant application has been found to reduce ethanol neurotoxicity, but the mechanisms by which this protection is afforded have not been defined. This study was designed to investigate the interactions between ethanol and the antioxidant vitamin E (alpha-tocopherol), with respect to neuronal survival and levels of proteins related to the Bcl-2 survival-regulatory gene family. Neonatal rat cerebellar granule cell cultures were used as a model system. It was found that ethanol significantly impaired neuronal survival in these preparations, and that survival in the presence of ethanol was enhanced by inclusion of vitamin E in the culture medium. This elevated survival was paralleled by increased levels of anti-apoptotic proteins (e.g., Bcl-2, Bcl-xl, activated Akt kinase), and concurrent downregulation of pro-apoptotic proteins (e.g., Bcl-xs). These results suggest that such alterations may represent an important mechanism whereby antioxidants protect against the neurotoxic effects of ethanol in the developing CNS. The possible manner by which these changes are effected are considered.