Sphingolipids in Ethanol-Induced Neuronal Apoptosis

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DESCRIPTION (provided by applicant): Ethanol-induced apoptotic neurodegeneration in the developing brain is considered a cause of fetal alcohol syndrome. Several studies using animal models indicate that sphingolipids (gangliosides, neutral glycosphingolipids, sphingomyelin, ceramide, etc.) mediate the cellular processes of survival and apoptosis. We hypothesize that ethanol-induced apoptosis in the developing brain is mediated or modified by cellular sphingolipids. Consequently, alteration of cellular sphingolipid profiles by the administration of exogenous sphingolipids or by the manipulation of endogenous sphingolipid metabolism would modify the ethanol-induced neurotoxicity. In Aim 1, we will test whether exogenous gangliosides and LIGA20 (a semisynthetic derivative of GM1 ganglioside) attenuate ethanol-induced neurodegeneration in the neonatal C57BL/6 mouse brain. We will also examine the effects of gangliosides and LIGA20 on ethanol-induced apoptosis using cultured cerebellar granule neurons obtained from C57BL76 mice. In Aim 2, in order to examine the hypothesis that ethanol-induced apoptosis is mediated or modified by endogenous sphingolipids, ethanol-induced changes in sphingolipid profiles and in metabolizing enzymes will be examined using animal and cell culture models. The effects of inhibitors of sphingolipid-metabolizing enzymes on ethanol-induced apoptosis will also be analyzed. Finally, based on the hypothesis that gangliosides alleviate ethanol-induced apoptosis through modifications of sphingolipid metabolism, the effects of gangliosides on sphingolipid profiles and related enzymes will be examined in the presence and absence of ethanol. These studies may identify sphingolipids as important factors affecting the ethanol-induced apoptotic pathway, and may lead to therapeutic applications of sphingolipids (or reagents affecting sphingolipid metabolism) that alleviate the adverse effects of ethanol on the developing brain.