Neuro-immunophyllin Ligand Mechanism of Action in Reducing Alcohol Preference

神经免疫茶素配体减少酒精偏好的作用机制

基本信息

批准号：
7388423
负责人：
THOMAS P BERESFORD
金额：
$ 18.11万
依托单位：
DENVER RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388423
关键词：
Abbreviations Abstinence Address Adult Adverse effects Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcoholic Beverages Alcohols American Animal Model Animal Testing Animals Antidepressive Agents Area Biological Blood Brain Calcineurin Calcineurin inhibitor Class Clinical Condition Consumption Control Animal Cyclosporine Desire for food Development Disease Disulfiram Dose Drug Kinetics Economic Burden Economics Effectiveness End Point Exhibits FK506 Future Goals Healed Health Human Immunosuppression Immunosuppressive Agents Investigation Journals Kinetics Lead Ligands Link Measures Medical Medical center Metabolic Methods Modeling Molecular Molecular Target Monitor Mus Naltrexone Nature Organ Transplantation Patients Persons Pharmaceutical Preparations Pilot Projects Population Postoperative Care Preparation Principal Investigator Process Productivity Property Range Rate Reporting Research Rewards Rodent Selective Serotonin Reuptake Inhibitor Self Administration Series Signal Transduction Solid Solutions Sucrose Testing Therapeutic immunosuppression Thinking Tissues Today Toxic effect Transplant Recipients Transplantation Variant acamprosate alcohol abstinence alcohol abuse therapy analog care burden clinical application consumption measures design drinking healing human subject in vivo liver transplantation mycophenolate mofetil preference prevent psychologic receptor research clinical testing research study social success

项目摘要

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.

描述（由申请人提供）：这项拟议的研究的长期目标是询问神经免疫蛋白配体的非免疫抑制剂是否可能有助于治疗酒精依赖性（AD）。广泛且临床上重要的问题是美国人口的7-10％，估计每年的经济负担超过1600亿美元。今天的AD治疗方法的选择很少是由于当前批准的药物的效力低。在过去的二十年中，神经免疫蛋白配体（例如环孢菌素A（CSA））已用于防止固体器官移植的组织排斥反应，包括为AD患者提供的肝移植，这是主要研究者的专业知识的AD患者。直到最近，在AD肝移植受者中，神经免疫蛋白配体暴露与同时且持续的戒酒发生率之间的神经免疫蛋白配体暴露率尚未建立联系：三年后的AD肝移植受者中的酒精含量高达70-75％。我们假设神经免疫性蛋白质配体暴露可能有助于这种作用。为了在受控的试点研究中对此进行测试，我们将CSA送给饮酒C57B1/6J小鼠。 CSA显着（P <0.0000），并持续降低处理过的小鼠的酒精偏好。（Beresford，HF，Deitrich，RA，Beresford。tp。Cyclosporine-A-A不鼓励C57B1/6J小鼠中的乙醇摄入量：一项初步研究。然而，我们观察到的偏好的显着和持续降低是否取决于大脑中钙调神经磷酸酶的抑制或免疫蛋白抑制，这是这类药理剂的两种主要已知作用机理。因此，拟议的研究将解决一系列免疫抑制剂的酒精偏好效应，以及一种CSA分子的一种非抑制性变体。我们假设只有与特定免疫蛋白受体相互作用的药物才能证明这种作用。这将在旨在评估的啮齿动物实验中进行测试1）钙调蛋白抑制或2）对于那些改变酒精偏爱的药物而言，免疫蛋白抑制可能是可能的作用机制。为了准备最终的人类应用，我们将表征啮齿动物中研究剂的动力学和毒性谱。我们预计我们的结果将导致神经免疫蛋白配体的临床应用，该配体没有免疫抑制特性，这些特性可能是有效治疗的人类AD的有效治疗方法。这项研究的未来方向将包括对基本研究成功的相关非免疫抑制剂的临床测试。