Estrogens for Alcoholism & Its Neurological Consequences

描述(申请人提供)：酒精滥用导致死亡率增加，神经功能障碍，以及治疗酒精中毒及其社会和医学后果的巨大社会成本。目前，还没有有效的疗法来治疗酒精中毒及其神经学后果。目前的拨款申请提出了一项研究计划，以评估雌激素治疗酒精戒断(EW)的行为和神经后果的有效性。基于我们大量的初步数据表明，雌激素可以减少戒断症状，改善小脑介导的行为结局，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对电子烟相关神经行为毒性的保护作用及其机制。我们将在这笔赠款中实现5个具体目标。具体目标1将确定雌激素对酒精依赖和EW期的影响。雄性和雌性大鼠将在依赖和戒断阶段暴露于17β-雌二醇(E_2)，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酒精戒断大鼠神经和行为障碍的保护作用。我们将使用一种新的雌激素，enatimer-E2，我们已经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将通过检测小脑组织中脂质过氧化产物丙二醛的最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将确定雌激素是否阻止乙醇戒断大鼠的氧化依赖核因子-kappaB(NFrkappaB)激活。特异靶5将确定雌激素诱导的蛋白激酶活性降低和Erki/2磷酸化在雌激素阻断EW期间NFrkappaB核转位中的作用。总的来说，拟议的研究将提供有关雌激素保护免受电子战后果的机制的新知识，并确定雌激素是否为酒精中毒及其后果的潜在药物疗法。

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withdrawal signs, improve cerebellar-mediated behavioral outcomes and protect cerebellar Purkinje cells of ethanol withdrawn rats, we propose studies to further determine the efficacy and mechanisms of estrogen protection against EW-related neurobehavioral toxicity.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Aim 2 will evaluate protective effects of nonfeminizing estrogens against neuronal and behavioral deficit in ethanol withdrawn rats.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Aim 4 will determine if estrogen prevents oxidant-dependent nuclear factor-kappa B (NFrkappaB) activation in ethanol withdrawn rats.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