Alcohol abuse causes increased mortality, neurological deficits and a huge cost to society to treat alcoholism, its social and medical consequences. Currently, there are no effective therapies for alcoholism and its neurological consequences. The present grant application proposes a research program to assess the efficacy of estrogens for treatment of the behavioral and neurological consequences of ethanol withdrawal (EW). Based upon our extensive preliminary data that indicate that estrogens reduce withdrawal signs, improve cerebellar-mediated behavioral outcomes and protect cerebellar Purkinje cells of ethanol withdrawn rats, we propose studies to further determine the efficacy and mechanisms of estrogen protection against EW-related neurobehavioral toxicity. We will achieve 5 specific aims in this grant.
Specific Aim 1 will determine estrogen effects on the ethanol dependence and the EW phase. Male and female rats will be exposed to 17beta-estradiol (E2) during the dependence versus the withdrawal phase to determine the stage of dependence/withdrawal that is most responsive to estrogens.
Specific Aim 2 will evaluate protective effects of nonfeminizing estrogens against neuronal and behavioral deficit in ethanol withdrawn rats. We will employ a novel estrogen, enatiomer-E2 that we have demonstrated to be neuroprotective in vitro and in vivo, but to lack estrogen receptor activity.
Specific Aim 3 will determine if estrogens antagonize the pro-oxidant effects of EW by assaying an end product of lipid peroxidation product, malondialdehyde, in cerebellar tissue.
Specific Aim 4 will determine if estrogen prevents oxidant-dependent nuclear factor-kappa B (NFrkappaB) activation in ethanol withdrawn rats.
Specific Aim 5 will determine the role of estrogen-induced reduction in protein kinase activity and ERKI/2 phosphorylation in the estrogen blockade of nuclear translocation of NFrkappaB during EW. Collectively, the proposed studies will provide new knowledge on the mechanism of estrogen protection from the consequences of EW and determine if estrogens are potential pharmacotherapies for alcoholism and its consequences ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013864-02
Application #
6855795
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Grandison, Lindsey
Project Start
2004-02-15
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$221,875
Indirect Cost
Name
University of North Texas
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Jung, Marianna E; Ju, Xiaohua; Simpkins, James W et al. (2011) Ethanol withdrawal acts as an age-specific stressor to activate cerebellar p38 kinase. Neurobiol Aging 32:2266-78
Jung, Marianna E; Wilson, Andrew M; Ju, Xiaohua et al. (2009) Ethanol withdrawal provokes opening of the mitochondrial membrane permeability transition pore in an estrogen-preventable manner. J Pharmacol Exp Ther 328:692-8
Prokai-Tatrai, Katalin; Prokai, Laszlo; Simpkins, James W et al. (2009) Phenolic compounds protect cultured hippocampal neurons against ethanol-withdrawal induced oxidative stress. Int J Mol Sci 10:1773-87
Jung, Marianna E; Simpkins, James W; Wilson, Andrew M et al. (2008) Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats. J Appl Physiol 105:510-7
Jung, Marianna E; Agarwal, Rajnee; Simpkins, James W (2007) Ethanol withdrawal posttranslationally decreases the activity of cytochrome c oxidase in an estrogen reversible manner. Neurosci Lett 416:160-4
Jung, Marianna E; Wilson, Andrew M; Simpkins, James W (2006) A nonfeminizing estrogen analog protects against ethanol withdrawal toxicity in immortalized hippocampal cells. J Pharmacol Exp Ther 319:543-50
Jung, Marianna Eunsun; Jacobs, Stephanie; Rewal, Mridula et al. (2005) Estradiol protects against alteration of protein kinase C(epsilon) in a binge model of ethanol dependence and withdrawal. Eur J Pharmacol 515:62-72
Rewal, Mridula; Wen, Yi; Simpkins, James W et al. (2005) Ethanol withdrawal reduces cerebellar parvalbumin expression in a manner reversed by estrogens. Neurosci Lett 377:44-8
Jung, M E; Gatch, M B; Simpkins, J W (2005) Estrogen neuroprotection against the neurotoxic effects of ethanol withdrawal: potential mechanisms. Exp Biol Med (Maywood) 230:8-22
Jung, Marianna E; Watson, David G; Simpkins, James W (2005) Suppression of protein kinase Cepsilon mediates 17beta-estradiol-induced neuroprotection in an immortalized hippocampal cell line. J Neurochem 95:745-55

Showing the most recent 10 out of 12 publications