Alcohol is a neuroteratogen;alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD), among which, fetal alcohol syndrome (FAS) is the most severe form. The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Glycogen synthase kinase 3? (GSK3?), a serine/threonine kinase, is an important mediator of neuron degeneration. We have demonstrated that ethanol activates GSK3?, and the activation of GSK3? leads to neuronal death. Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity. We have purified a potent antioxidant from blackberries, cyanidin-3-glucoside (C3G). Our study indicates that C3G inhibits GSK3? activity and alleviates oxidative stress in cultured neuronal cells. In addition, C3G protects neuronal cells against ethanol-induced cell death. C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3? inhibitors. C3G can cross the blood brain barrier (BBB) and distribute in the brain. C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain. Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (iv) injection in animals, and no adverse effect is observed. These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage. We hypothesize that C3G's potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling, GSK3?/Bax pathways. To test the hypothesis, we will (1) investigate the antioxidant property of C3G and its metabolites, and their effects on GSK3? activity;(2) determine whether C3G protection against ethanol- induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3?;(3) determine whether C3G ameliorates ethanol-induced behavioral deficits. C3G is a potent natural antioxidant and has diverse potential benefits for human health. It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3? inhibitor. As a unit, the proposed experiments will elucidate the novel role of C3G, and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity. Our study will potentially offer a new therapeutic strategy.

Public Health Relevance

Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD); among which; fetal alcohol syndrome (FAS) is the most severe form. The developing central nervous system (CNS) is particularly sensitive to ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Both glycogen synthase kinase 3 (GSK3 ) and oxidative stress contributes to ethanol neurotoxicity. We have purified a potent antioxidant from blackberries; cyanidin-3-glucoside (C3G) which can also inhibit GSK3 and reduce oxidative stress. The current study is to determine whether C3G ameliorates ethanol-induced neuronal loss as well as behavioral deficits. The proposal will potentially develop a new therapeutic strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015407-10
Application #
8617197
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Regunathan, Soundar
Project Start
2004-12-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2014
Total Cost
$347,141
Indirect Cost
$113,376
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Wang, Haiping; Ke, Zunji; Alimov, Alexander et al. (2014) Spatiotemporal expression of MANF in the developing rat brain. PLoS One 9:e90433
Ji, Zhe; Fan, Zhiqin; Zhang, Ying et al. (2014) Thiamine deficiency promotes T cell infiltration in experimental autoimmune encephalomyelitis: the involvement of CCL2. J Immunol 193:2157-67
Liu, M; Alimov, A P; Wang, H et al. (2014) Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK. Neuroscience 267:102-13
Meng, Ya; Yong, Yue; Yang, Guang et al. (2013) Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism. J Neurochem 126:805-18
Wang, Haiping; Bower, Kimberly A; Frank, Jacqueline A et al. (2013) Hypoxic preconditioning alleviates ethanol neurotoxicity: the involvement of autophagy. Neurotox Res 24:472-7
Alimov, Alexander; Wang, Haiping; Liu, Mei et al. (2013) Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods. Metab Brain Dis 28:667-76
Luo, Jia (2012) Mechanisms of ethanol-induced death of cerebellar granule cells. Cerebellum 11:145-54
Yong, Yue; Ding, Hanqing; Fan, Zhiqin et al. (2011) Lithium fails to protect dopaminergic neurons in the 6-OHDA model of Parkinson's disease. Neurochem Res 36:367-74
Yang, Guang; Meng, Ya; Li, Wenxia et al. (2011) Neuronal MCP-1 mediates microglia recruitment and neurodegeneration induced by the mild impairment of oxidative metabolism. Brain Pathol 21:279-97
Zhang, Qipeng; Yang, Guang; Li, Wenxia et al. (2011) Thiamine deficiency increases ýý-secretase activity and accumulation of ýý-amyloid peptides. Neurobiol Aging 32:42-53

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