Neuro-immunophyllin Ligand Mechanism of Action in Reducing Alcohol Preference

描述(由申请人提供)：这项拟议研究的长期目标是询问神经免疫茶素配体的非免疫抑制同系物是否在治疗酒精依赖(AD)方面有用。阿尔茨海默病是一个普遍存在的临床重要问题，影响着美国7%-10%的人口，估计每年造成超过1600亿美元的经济负担。由于目前批准的药物疗效较低，目前治疗AD的药物选择很少。神经免疫球蛋白配体，如环孢素A(CsA)，在过去的20年里一直被用于防止实体器官移植的组织排斥反应，包括为AD患者提供的肝移植，这是首席研究员的专长领域。直到最近，在多个中心报道的AD肝移植受者中，神经免疫球蛋白配体暴露与同时高且持续的戒酒率之间没有联系：三年后戒酒率高达70%-75%。我们推测，神经免疫球蛋白配体的暴露可能有助于这种效应。为了在对照的先导研究中验证这一点，我们给饮酒的C57b1/6J小鼠注射环孢素A。CsA显著(p&lt；0.0000)并持续降低了治疗小鼠的酒精偏好。(Beresford，HF，Deitrich，RA，Beresford。TP.环孢素-A抑制C57b1/6J小鼠酒精摄入的初步研究《酒精研究杂志》，2005年9月)。然而，目前尚不清楚我们观察到的偏好的显著和持续减少是否取决于大脑中钙调神经磷酸酶抑制或免疫叶绿素抑制，这是这类药物已知的两种主要作用机制。因此，拟议的研究将解决一系列免疫抑制剂以及CsA分子的一个非抑制性变体的酒精偏好效应。我们假设，只有与特定免疫茶素受体相互作用的药物才能证明这一效应。这将在啮齿动物实验中进行测试，旨在评估1)钙调神经磷酸酶抑制或2)免疫叶绿素抑制是否可能是那些改变酒精偏好的药剂的作用机制(S)。在为最终的人类应用做准备时，我们将表征这些研究试剂在啮齿动物身上的动力学和毒性分布。我们预计，我们的结果将导致无免疫抑制特性的神经免疫茶素配体的临床应用，这可能是治疗人类阿尔茨海默病的有效方法(S)。这项研究的未来方向将包括基础研究认为成功的相关非免疫抑制剂的临床测试。

DESCRIPTION (provided by applicant): The long term goal of this proposed study is to ask whether non-immunosuppressant congeners of the neuro-immunophyllin ligands may be useful in the treatment of alcohol dependence (AD). A widespread and clinically important problem, AD affects 7-10% of the U.S. population and carries an estimated economic burden of more than $160 billion annually. Medication choices for the treatment of AD today are few due to low efficacy of currently approved agents. Neuro-immunophyllin ligands, such as cyclosporine-A (CsA), have been used in preventing tissue rejection in solid organ transplantation for the past twenty years, including liver transplants provided for AD patients, an area of the Principal Investigator's expertise. Until recently, no connection was made between neuro-immunophyllin ligand exposure and concurrently high, and sustained, rates of abstinence from alcohol among AD liver transplant recipients reported across centers: rates as high as 70-75% after three years. We hypothesized that neuro-immunophyllin ligand exposure might contribute to this effect. To test this in controlled pilot study, we gave CsA to alcohol drinking C57b1/6j mice. CsA significantly (p<0.0000) and persistently reduced alcohol preference in the treated mice. (Beresford, HF, Deitrich, RA, Beresford. TP. Cyclosporine-A Discourages Ethanol Intake In C57b1/6j Mice: a Preliminary Study. Journal of Studies on Alcohol, September, 2005). It is not known, however, whether the significant and sustained reduction in preference that we observed depends on calcineurin inhibition or immunophyllin inhibition in the brain, two of the principal known mechanisms of action of this class of pharmacologic agents. Therefore, the proposed investigation will address the alcohol preference effects of a series of immunosuppressant agents, as well as one non-suppressive variant of the CsA molecule. We hypothesize that only agents interacting with specific immunophyllin receptors will demonstrate this effect. This will be tested in rodent experiments designed to assess 1) whether calcineurin inhibition or 2) immunophyllin inhibition may be possible mechanism(s) of action for those agents that alter alcohol preference. In preparation for eventual human application, we will characterize the kinetic and toxicity profiles of the study agents in rodents. We anticipate that our results will lead to a clinical application of neuro-immunophyllin ligands free of immuno-suppressive properties that may be effective treatment(s) for AD in humans. The future direction of this study will include clinical testing of related non-immunosuppressant agents that basic investigations deem successful.