Neuro-immunophyllin Ligand Mechanism of Action in Reducing Alcohol Preference

描述（由申请人提供）：本研究的长期目标是研究神经免疫叶绿素配体的非免疫抑制同源物是否可用于治疗酒精依赖（AD）。阿尔茨海默病是一个广泛存在的重要临床问题，影响了美国7-10%的人口，每年造成的经济负担估计超过1600亿美元。由于目前批准的药物疗效低，目前用于治疗AD的药物选择很少。神经免疫phyllin配体，如环孢素- a (CsA)，在过去的二十年中已被用于防止实体器官移植中的组织排斥，包括为AD患者提供的肝脏移植，这是首席研究员的专业领域。直到最近，在各中心报告的阿尔茨海默病肝移植受者中，神经免疫phyllin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%。我们假设神经免疫叶绿素配体暴露可能有助于这种效果。为了在对照试验中验证这一点，我们给饮酒的C57b1/6j小鼠注射了CsA。CsA显著（p<0.0000）并持续降低了小鼠的酒精偏好。(贝雷斯福德，HF, Deitrich， RA，贝雷斯福德。TP。环孢素a抑制C57b1/6j小鼠乙醇摄入的初步研究《酒精研究杂志》，2005年9月)。然而，尚不清楚我们观察到的显著和持续的偏好降低是否取决于脑内钙调神经磷酸酶抑制或免疫phyllin抑制，这是这类药物的两种已知的主要作用机制。因此，本研究将探讨一系列免疫抑制剂的酒精偏好效应，以及CsA分子的一种非抑制性变体。我们假设只有与特异性免疫phyllin受体相互作用的药物才会表现出这种效果。这将在啮齿类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phyllin抑制是否可能是这些改变酒精偏好的药物的作用机制。为了准备最终的人类应用，我们将描述研究剂在啮齿动物中的动力学和毒性特征。我们预计，我们的研究结果将导致无免疫抑制特性的神经免疫phyllin配体的临床应用，这可能是治疗人类AD的有效方法。本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试验。

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.