SSRI-neuroprotection for HIV/drug abuse

SSRI-针对 HIV/药物滥用的神经保护

• 批准号: 7494352
• 负责人: AVINDRA NATH
• 金额: $ 36.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494352
• 关键词: AIDS Dementia Complex; Address; Animal Model; Anti-Retroviral Agents; Antidepressive Agents; Astrocytes; Brain; Calcium Channel; Cell physiology; Class; Clinical Research; Clinical Trials; Cocaine; Communities; Developed Countries; Developing Countries; Face; Fluoxetine; Future; Growth Factor; HIV; HIV Infections; HIV therapy; Hawaii; Human; Injury; Magnetic Resonance Spectroscopy; Mediating; Morbidity - disease rate; N-acetylaspartate; Neurocognitive; Neuroglia; Neurons; Numbers; Opiates; Oxidative Stress; Paroxetine; Pathogenesis; Patients; Personal Communication; Pharmaceutical Preparations; Population; Production; Property; Proteins; Public Health; Research; Research Design; Research Personnel; Stem cells; United States; Universities; Viral; Viral Load result; cell type; chemokine; cytokine; design; drug abuser; drug of abuse; inhibitor/antagonist; macrophage; mitochondrial dysfunction; nerve injury; nerve stem cell; neuron loss; neuroprotection; neurotoxicity; novel; novel therapeutics; preclinical study; research study; serotonin transporter

DESCRIPTION (provided by applicant): HIV infection in United States and several other developed countries is now largely driven by drug abusing populations. Since both HIV and drugs of abuse independently cause injury to the brain, researchers face multiple challenges in the design of studies to address the pathogenesis or develop effective therapies. This is further complicated by the fact that these patients often abuse multiple drugs and have other co-morbidities. Nonetheless, it is clear that the use of antiretroviral drugs alone is not sufficient and neuroprotective strategies need to be used in these patient populations. Yet no clinical trials have been conducted to date in this patient population. On the contrary, drug abusers have been excluded from most clinical trials on HIV dementia. While the research community recognizes the importance of studying the combined effects of these substances challenges faced include the large number of variables that need to be considered and the lack of ideal small animal models to study these combined effects. Despite these drawbacks, we rationalize that information available to date clearly suggests that there are common subcellular mechanisms involved in neural injury by HIV proteins and drugs of abuse, which can be exploited to develop novel therapeutic approaches for this patient population. HIV proteins and select drugs of abuse may contribute to the pathogenesis of HIVD through non-mutually exclusive mechanisms including 1) direct neurotoxicity, 2) glial activation, and 3) increased viral replication. We recently screened over 2000 compounds that have been approved by the Federal Drug Administration for human use and found that two compounds within the class of the selective serotinergic release inhibitors (SSRI), fluoxetine and paroxetine, have potent neuroprotective effects against the combined effects of drugs of abuse and HIV proteins. Interestingly, in a recent retrospective clinical study it was found that HIV patients on antidepressants had better neurocognitive function and lower CSF viral loads (Letendre et al, 2007). In another study with magnetic resonance spectroscopy, HIV infected patients on SSRIs had higher levels of N-acetyl aspartate suggestive of neuroprotection (Linda Chang, University of Hawaii, personal communication). For these reasons, we have designed an experimental study to determine if fluoxetine and paroxetine can impact the combined effects of HIV and drugs of abuse in various cell types in the brain and determine the mechanisms by which such neuroprotection may occur. Another novel aspect of our study is that we will study the combined effects of opiates and cocaine, since they are commonly used together. Thus this study will provide critical information needed to design future clinical trials with these agents for HIV infected drug abusers. We propose three specific aims. (1). Determine if SSRI can modulate the effect of HIV proteins and drugs of abuse on neuronal function (2) Determine if SSRI can modulate effects of HIV proteins and drugs of abuse on glial cell function (3) Determine if SSRI can modulate the effect of HIV proteins and drugs of abuse on neural progenitor cell function. PUBLIC HEALTH RELEVANCE Currently, there is no available neuroprotective therapy for HIV infected drug abusers who may be afflicted by a dementing illness. We have screened over 2,00 compounds and identified a class of antidepressant compounds that have novel brain protective properties. We will explore their mechanism of action and conduct other preclinical studies that are needed to take them to clinical trials.

描述（由申请人提供）：美国和其他几个发达国家的艾滋病毒感染现在主要是由滥用毒品的人群驱动的。由于艾滋病毒和虐待药物都独立造成了大脑伤害，因此研究人员在研究发病机理或开发有效疗法的研究时面临多重挑战。这些患者经常滥用多种药物并具有其他合并症，这更加复杂。尽管如此，很明显，仅使用抗逆转录病毒药物就不够，并且需要在这些患者种群中使用神经保护策略。然而，迄今为止，该患者人群尚未进行临床试验。相反，毒品滥用者已被排除在大多数关于HIV痴呆症的临床试验之外。尽管研究界认识到研究这些物质挑战所面临的综合作用的重要性，包括需要考虑的大量变量以及缺乏理想的小动物模型来研究这些综合效果。尽管存在这些缺点，但我们合理化了迄今为止可用的信息清楚地表明，艾滋病毒蛋白和滥用药物涉及神经损伤的常见亚细胞机制，可以利用这些机制为该患者人群开发新的治疗方法。 HIV蛋白和精选滥用药物可能通过非缺乏排他性的机制（包括1）直接神经毒性，2）胶质激活和3）增加病毒复制来有助于HIVD的发病机理。最近，我们筛选了2000多种化合物，这些化合物已获得人类使用的联邦药物管理局批准，发现选择性性血清素能释放抑制剂（SSRI），氟西汀和帕罗西汀的两种化合物具有有效的神经保护作用，以抗滥用和HIV蛋白药物的综合作用。有趣的是，在最近的回顾性临床研究中，发现抗抑郁药的HIV患者具有更好的神经认知功能和较低的CSF病毒载量（Letendre等，2007）。在另一项有关磁共振光谱的研究中，SSRI的HIV感染患者具有较高水平的N-乙酰天冬氨酸含量提示神经保护作用（夏威夷大学Linda Chang，个人交流）。由于这些原因，我们设计了一项实验研究，以确定氟西汀和帕罗西汀是否会影响大脑中各种细胞类型的艾滋病毒和滥用药物的综合作用，并确定可能发生这种神经保护的机制。我们研究的另一个新方面是，我们将研究阿片类药物和可卡因的综合作用，因为它们通常在一起使用。因此，这项研究将提供与这些药物一起设计未来临床试验所需的关键信息，以供艾滋病毒感染的毒品滥用者。我们提出了三个具体目标。 （1）。确定SSRI是否可以调节HIV蛋白和滥用药物对神经元功能的影响（2）确定SSRI是否可以调节HIV蛋白和滥用药物对神经胶质细胞功能的影响（3）确定SSRI是否可以调节HIV蛋白和滥用药物对神经祖细胞功能的影响。目前，公共卫生的相关性尚无针对艾滋病毒感染的滥用毒品的可用神经保护疗法，他们可能患有痴呆症。我们已经筛选了2,00多种化合物，并鉴定了一类具有新型脑保护特性的抗抑郁药。我们将探索他们的作用机理，并进行其他临床前研究，以将其带到临床试验。