Estrogens for Alcoholism & Its Neurological Consequences

雌激素治疗酗酒

基本信息

批准号：
7174234
负责人：
JAMES W. SIMPKINS
金额：
$ 21.04万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-15 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7174234
关键词：
Abbreviations Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholism Animal Model Antioxidants Applications Grants Attenuated Behavior Therapy Behavior assessment Behavioral Binding Biological Assay Brain region C-terminal Cell Nucleus Cerebellum Cerebral Ischemia Chronic Complement Factor B Conditioned Stimulus DNA DNA Nucleotidylexotransferase Data Dependence Dextrins Dissociation Estradiol Estrogen Receptors Estrogens Ethanol Ethanol dependence Extracellular Signal Regulated Kinases Female Fluorescein Fluoresceins Genes Goals Grant High Pressure Liquid Chromatography Human In Vitro Individual Knowledge Label Lipid Peroxidation Malondialdehyde Mediating Mediation Medical Mitogen-Activated Protein Kinases Modeling Molecular Mutation NF-kappa B Nerve Degeneration Neurologic Neurons Nuclear Nuclear Translocation Outcome Oxidants Oxidative Stress Phase Phosphorylation Phosphotransferases Prevention Production Protein Isoforms Protein Kinase Protein Kinase C Proteins Purkinje Cells Rattus Reactive Oxygen Species Reporting Research Role Signal Transduction Societies Staging Steroids Stimulus Substance Withdrawal Syndrome Tissues Toxic effect Withdrawal alcoholism pharmacotherapy alcoholism therapy base cost dextrin enantiomer improved in vitro Model in vivo in vivo Model inhibitor/antagonist male mortality neurobehavioral neurotoxicity novel prevent problem drinker programs protective effect social tissue culture transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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withdrawal signs, improve cerebellar-mediated behavioral outcomes and protect cerebellar Purkinje cells of ethanol withdrawn rats, we propose studies to further determine the efficacy and mechanisms of estrogen protection against EW-related neurobehavioral toxicity.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

描述（由申请人提供）：酗酒会导致死亡率增加、神经功能缺陷以及治疗酗酒及其社会和医疗后果的巨大社会成本。目前，还没有针对酗酒及其神经系统后果的有效疗法。本拨款申请提出了一项研究计划，以评估雌激素对治疗乙醇戒断（EW）的行为和神经系统后果的功效。基于我们广泛的初步数据表明雌激素可以减少戒断症状，改善小脑介导的行为结果并保护乙醇戒断大鼠的小脑浦肯野细胞，我们建议进行研究以进一步确定雌激素针对 EW 相关神经行为毒性的功效和机制。我们将通过这笔赠款实现 5 个具体目标。具体目标 1 将确定雌激素对乙醇依赖性和 EW 阶段的影响。雄性和雌性大鼠在依赖阶段与戒断阶段接触17β-雌二醇（E2），以确定对雌激素最敏感的依赖/戒断阶段。具体目标 2 将评估非女性化雌激素对乙醇戒断大鼠神经元和行为缺陷的保护作用。我们将采用一种新型雌激素，即对映异构体-E2，我们已证明它在体外和体内具有神经保护作用，但缺乏雌激素受体活性。具体目标 3 将通过测定小脑组织中脂质过氧化产物丙二醛的终产物来确定雌激素是否拮抗 EW 的促氧化作用。具体目标 4 将确定雌激素是否会阻止乙醇戒断大鼠中氧化剂依赖性核因子 kappa B (NFrkappaB) 的激活。具体目标 5 将确定雌激素诱导的蛋白激酶活性降低和 ERKI/2 磷酸化在 EW 期间雌激素阻断 NFrkappaB 核易位中的作用。总的来说，拟议的研究将提供关于雌激素保护免受电子战后果的机制的新知识，并确定雌激素是否是酗酒及其后果的潜在药物疗法