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询问神经免疫叶素配体的非免疫抑制剂同源物是否可用于治疗酒精依赖（AD）。AD是一个广泛的临床重要问题，影响7-10%的美国人口，估计每年的经济负担超过1600亿美元。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。神经免疫叶素配体，如环孢菌素-A（CsA），在过去的二十年中已用于预防实体器官移植中的组织排斥反应，包括为AD患者提供的肝移植，这是主要研究者的专业领域。直到最近，在各中心报告的AD肝移植受者中，神经免疫叶素配体暴露与同时高且持续的戒酒率之间没有联系：三年后的戒酒率高达70-75%。我们推测，神经免疫叶素配体暴露可能有助于这种效果。为了在对照试验研究中测试这一点，我们给饮酒的C57 b1/6 j小鼠注射CsA。CsA显著（p<0.0000）和持续降低治疗小鼠的酒精偏好。（Beresford，HF，Deitrich，RA，Beresford. TP.环孢素A抑制C57 b1/6 j小鼠的乙醇摄入：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偏好的显著和持续降低是否取决于脑中的钙调磷酸酶抑制或免疫叶素抑制，这是这类药物的两种主要已知作用机制。因此，拟议的研究将解决一系列免疫抑制剂以及CsA分子的一种非抑制性变体的酒精偏好效应。我们假设，只有与特异性免疫叶素受体相互作用的药物才会显示这种作用。这将在啮齿动物实验中进行测试，该实验旨在评估1）钙调磷酸酶抑制或2）免疫叶素抑制是否可能是改变酒精偏好的药物的可能作用机制。在准备最终的人类应用中，我们将表征研究药物在啮齿动物中的动力学和毒性特征。我们预期我们的结果将导致无免疫抑制特性的神经免疫叶素配体的临床应用，其可能是人类AD的有效治疗。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.