Alcohol-Induced Neuroinflammation and AUD Therapeutic Mechanisms

摘要 酒精使用障碍（AUD）是一种异质性疾病， 遗传和环境因素。迫切需要开发新的、潜在的、广泛有效的 药物治疗酒精是一种高度促炎的分子，这是酒精发病机制的关键。 导致组织损伤。申请人和合作者的工作已经确定了3种候选药物， 可能至少部分通过减少神经炎症起作用的AUD的重新定位。它们包括 pannexin1通道的抑制剂，已成为神经炎症的主要驱动因素， 糖皮质激素信号调节剂，对炎症有复杂作用。事实上，慢性 糖皮质激素导致神经炎症和神经元损伤，其导致AUD和 神经退行性疾病总的来说，这些考虑支持靶向炎症和炎症反应。 AUD相关组织损伤。然而，酒精引起的一些炎症信号机制， 如Toll样受体4，已被证明不会改变酒精摄入。因此，最重要的是描绘 动机和治疗意义的炎症机制。为此，《公约》中的具体目标1 本提案将测试代表性抗炎药的作用，包括直接和间接抗炎药， 具有不同作用机制的炎性小体抑制剂在已建立的大鼠非依赖性 依赖性酒精摄入，其特征是饮酒量增加， 因为它被证明对几乎所有在人AUD中显示出前景的药物的作用敏感。相互关联 《特定目标2》中的研究将剖析酒精和正在研究的治疗方法对 神经炎症、炎性体调节以及星形胶质细胞和小胶质细胞调节，以确定关键指标 酒精诱导的神经炎症以及测试中药物的作用机制， 确定其有效性或缺乏有效性的分子基础，并发现潜在的新的 AUD的治疗目标。 总之，这项研究的结果将促进我们对治疗机制的理解 反应性或缺乏反应性以及具有治疗意义的酒精诱导的组织损伤，以及 将指出新的治疗目标，更具体和有效的药物，以改善 神经炎症和组织损伤，并减少过量饮酒。

Abstract Alcohol use disorder (AUD) is a heterogeneous condition resulting from the interplay of neurobiological, genetic, and environmental factors. There is pressing need to develop new and, potentially, broadly effective medications. Alcohol is a highly pro-inflammatory molecule, which is key in the pathogenesis of alcohol- induced tissue damage. Work by the applicants and collaborators has identified 3 candidate drugs for repositioning for AUD that are likely to act at least in part via reduction of neuroinflammation. They include inhibitors of the pannexin1 channel, which has emerged as a major driver of neuroinflammation, and modulators of glucocorticoid signaling, that has a complex action on inflammation. In fact, chronic glucocorticoids result in neuroinflammation and neuronal damage that contribute to both AUD and neurodegenerative diseases. Collectively, these considerations support targeting inflammation and the associated tissue damage for AUD. However, some inflammatory signaling mechanisms recruited by alcohol, such as the Toll-like receptor 4, have proven not to modify alcohol intake. Thus, it is paramount to delineate the inflammatory mechanisms of motivational and therapeutic significance. To this end, Specific Aim 1 in the present proposal will test the effects of representative anti-inflammatory drugs including direct and indirect inflammasome inhibitors with different mechanisms of action in an established rat paradigm of non-dependent and dependent alcohol intake, which is characterized by escalated alcohol drinking and is highly translational as it proved sensitive to the action of virtually all drugs that have shown promise in human AUD. Interlinked studies in Specific Aim 2 will dissect the effects of alcohol and the therapeutics under study on neuroinflammation, inflammasome regulation and astrocyte and microglia regulation to identify key indicators of alcohol-induced neuroinflammation as well as the mechanisms of action of the drugs under testing to determine the molecular bases of their effectiveness or lack thereof as well as to uncover potential new therapeutic targets for AUD. Altogether, the results of this study will advance our understanding of the mechanisms behind treatment responsiveness or lack thereof as well as of alcohol-induced tissue damage of therapeutic significance, and will point to new therapeutic targets for more specific and effective medications to ameliorate neuroinflammation and tissue damage in the setting of AUD and reduce excessive alcohol consumption.