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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA015355-01A1
Application #
6968021
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Sorensen, Roger
Project Start
2005-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$167,299
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
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Yang, Dun-Sheng; Stavrides, Philip; Saito, Mitsuo et al. (2014) Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain 137:3300-18
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Sadrian, Benjamin; Wilson, Donald A; Saito, Mariko (2013) Long-lasting neural circuit dysfunction following developmental ethanol exposure. Brain Sci 3:704-27
Saito, Mitsuo; Chakraborty, Goutam; Shah, Relish et al. (2012) Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain. J Neurochem 121:649-61
Chakraborty, Goutam; Saito, Mitsuo; Shah, Relish et al. (2012) Ethanol triggers sphingosine 1-phosphate elevation along with neuroapoptosis in the developing mouse brain. J Neurochem 121:806-17
Sadrian, B; Subbanna, S; Wilson, D A et al. (2012) Lithium prevents long-term neural and behavioral pathology induced by early alcohol exposure. Neuroscience 206:122-35
Wilson, Donald A; Peterson, Jesse; Basavaraj, Balapal S et al. (2011) Local and regional network function in behaviorally relevant cortical circuits of adult mice following postnatal alcohol exposure. Alcohol Clin Exp Res 35:1974-84
Saito, Mariko; Chakraborty, Goutam; Mao, Rui-Fen et al. (2010) Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain. Neurochem Res 35:651-9

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