Ethanol Withdrawal, Stress and Polyamine Neuroprotection

描述（由申请方提供）：尚不完全了解乙醇戒断诱导神经毒性的机制和逆转这种损伤的方法。研究表明，糖皮质激素和多胺可能有助于乙醇相关的神经变性。因此，广泛的，长期的目标，这一建议是建立更精确的机制，涉及糖皮质激素诱导的乙醇戒断（EWD）介导的损害加重使用器官型海马切片文化。为此，将培养物长期暴露于乙醇，并在皮质酮存在下取出。然后使用非活体荧光染料碘化丙啶评估毒性。一些研究表明，EWD诱导的损伤可能部分通过激活NMDA受体的多胺敏感部分介导。此外，皮质酮给药也可能影响这种多胺敏感亚基的表达。将使用亚精胺增强[125 I]MK-801结合的放射自显影成像来检验这些假设。次要的但治疗相关的目的是检查新的NMDA多胺位点和糖皮质激素受体拮抗剂对皮质酮增强EWD诱导的毒性的功效。无论拟议研究的结果如何，它们都可能为EWD介导的海马变性的一些机制提供相当多的见解，并确定治疗酒精相关神经变性的潜在治疗靶点。

DESCRIPTION (provided by applicant): Mechanisms underlying ethanol withdrawal-induced neurotoxicity and means to reverse this damage are not completely understood. Research suggests that glucocorticoids and polyamines may contribute to ethanol-associated neurodegeneration. Thus, the broad, long-term objective of this proposal is to establish more precisely the mechanisms involving glucocorticoid-induced exacerbation of ethanol withdrawal (EWD)-mediated damage using organotypic hippocampal slice cultures. To this end, cultures will be exposed chronically to ethanol and withdrawn in the presence of corticosterone. Toxicity will then be assessed using the non-vital fluorescent dye propidium iodide. Some studies suggest that EWDinduced damage may be partially mediated via activation of the polyamine-sensitive portion of NMDA receptors. In addition, corticosterone administration may also influence expression of this polyaminesensitive subunit. These hypotheses will be tested using autoradiographic imaging of spermidine's potentiation of [125l]MK-801 binding. The secondary yet therapeutically relevant objective is to examine the efficacy of novel NMDA polyamine-site and glucocorticoid receptor antagonists against corticosterone's potentiation of EWD-induced toxicity. Regardless of the outcomes of the proposed studies, they may provide considerable insight into some of the mechanisms of EWD-mediated hippocampal degeneration, as well as identify potential therapeutic targets for the treatment of alcohol-associated neurodegeneration.