SSRI-neuroprotection for HIV/drug abuse

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吸毒人群驱动的。由于艾滋病毒和滥用药物都独立地对大脑造成损伤，研究人员在设计研究以解决发病机制或开发有效疗法方面面临着多重挑战。这是进一步复杂的事实，这些患者往往滥用多种药物，并有其他合并症。然而，很明显，单独使用抗逆转录病毒药物是不够的，需要在这些患者人群中使用神经保护策略。然而，迄今为止尚未在该患者人群中进行临床试验。相反，药物滥用者被排除在艾滋病毒痴呆症的大多数临床试验之外。虽然研究界认识到研究这些物质的综合效应的重要性，但面临的挑战包括需要考虑大量变量以及缺乏理想的小动物模型来研究这些综合效应。尽管有这些缺点，我们合理化，迄今为止的信息清楚地表明，有共同的亚细胞机制参与神经损伤的艾滋病毒蛋白和药物滥用，可以利用开发新的治疗方法，为这一患者群体。HIV蛋白质和选定的滥用药物可能通过非相互排斥的机制促进HIVD的发病机制，包括1）直接神经毒性，2）神经胶质活化，3）病毒复制增加。我们最近筛选了超过2000种已被联邦药物管理局批准用于人类使用的化合物，并发现选择性乙酰胆碱能释放抑制剂（SSRI）类中的两种化合物，氟西汀和帕罗西汀，对滥用药物和HIV蛋白的联合作用具有有效的神经保护作用。有趣的是，在最近的一项回顾性临床研究中，发现接受抗抑郁药治疗的HIV患者具有更好的神经认知功能和更低的CSF病毒载量（Letendre et al，2007）。在另一项磁共振波谱研究中，接受SSRIs治疗的HIV感染患者的N-乙酰天冬氨酸水平较高，提示有神经保护作用（琳达·张，夏威夷大学，个人交流）。出于这些原因，我们设计了一项实验研究，以确定氟西汀和帕罗西汀是否可以影响HIV和药物滥用在大脑中各种细胞类型中的联合作用，并确定这种神经保护可能发生的机制。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联合作用，因为它们通常一起使用。因此，这项研究将提供关键信息，需要设计未来的临床试验与这些药物的艾滋病毒感染的药物滥用者。我们提出三个具体目标。（一）.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。公共卫生相关性目前，对于可能患有痴呆症的HIV感染药物滥用者，没有可用的神经保护疗法。我们已经筛选了2000多种化合物，并确定了一类具有新的大脑保护特性的抗抑郁化合物。我们将探索它们的作用机制，并进行其他临床前研究，这些研究是将它们带入临床试验所必需的。

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.