Endocannabinoids, Cannabis, and Neurocognitive Deficits in HIV

内源性大麻素、大麻和艾滋病毒的神经认知缺陷

基本信息

批准号：
8920534
负责人：
Brook Henry
金额：
$ 22.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-03 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8920534
关键词：
2-arachidonylglycerol Address Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Attenuated Biological Markers Biological Process Brain CCL2 gene CD4 Positive T Lymphocytes CNR2 gene Cannabis Cannabis Abuse Cells Cerebrospinal Fluid Chronic Cognition Cognitive Dependence Deterioration Development Diagnosis Disease Drug usage Endocannabinoids Endothelin-1 Enzymes Exhibits HIV HIV Seropositivity HIV-1 HIV-associated neurocognitive disorder Health Human Immune Impaired cognition Individual Inflammation Inflammatory Intercellular adhesion molecule 1 Knowledge Life Ligands Light Link Lipase Marijuana Dependence Mediating Medical Marijuana Microglia Multiple Sclerosis Mus Nervous System Trauma Neuraxis Neurocognitive Neurocognitive Deficit Neurodegenerative Disorders Nitric Oxide Oxidative Stress Participant Pathogenesis Patients Performance Peripheral Pharmaceutical Preparations Plasma Play Population Process Property Proteins Reporting Role Schizophrenia T-Lymphocyte Testing Therapeutic Time Tumor Necrosis Factor-alpha Virus Work anandamide cytokine endogenous cannabinoid system fatty acid amide hydrolase functional disability immune function improved inhibitor/antagonist marijuana use marijuana user meetings monocyte neurobiological mechanism neuroinflammation neuropathology neurotoxic pre-clinical preclinical study prevent receptor expression

项目摘要

DESCRIPTION: The endocannabinoid (EC) system plays a critical role in the pathogenesis of neuroinflammatory and neurodegenerative disorders, including regulating pro-inflammatory cytokines, endothelial activation, and oxidative stress. Over the past decade, preclinical studies have indicated that the anti-inflammatory and neuroprotective properties of the EC system, including activation of the EC CB2 receptor, may have therapeutic utility in reducing HIV-induced damage to the central nervous system (CNS) and preventing the development of HIV-associated neurocognitive disorders (HAND). In contrast, exogenous cannabis use is reported to induce neurocognitive and functional impairment after chronic exposure. Although the neurobiological mechanisms underlying these effects remain speculative, cannabis exposure reduces EC ligand and receptor expression in both humans and mice, suggesting that disruption of the EC system may play a critical role in the detrimental effects of this drug. While recent work indicates that exogenous cannabis can block upregulated EC activity in schizophrenia patients, the individual and combined effects of HIV and cannabis use on the EC system have not been characterized, representing a fundamental gap in our knowledge. Thus, this application will examine the relationship between cannabis use, EC function, and mechanisms of HIV-related pathogenesis implicated in the development of HAND. We will quantify cerebrospinal fluid (CSF) and plasma levels of the two primary endocannabinoid ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in HIV- and HIV+ participants (n of 50 per group) with no cannabis use (d 5 times over lifetime), light cannabis use (1-4 times per month in past year), and heavy cannabis use (>10 times per month in past year and meeting criteria for lifetime cannabis abuse or dependence). To assess potential mechanisms of HIV-EC interaction, we will also examine expression of the CB2 receptor in monocytes and T- cells, as well as the EC ligand deactivation enzymes fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase (MAGL). We propose that EC ligand and receptor expression will be elevated in cannabis-naive HIV+ participants as a compensatory protective mechanism, but decline in participants with heavy cannabis use. We will also test the hypothesis that higher levels of AEA, 2-AG and CB2 expression will be associated with lower levels of neuroinflammatory markers, endothelial activation, and oxidative stress. Finally, we propose that heavy cannabis use will impair neurocognitive performance compared to no cannabis use in HIV+ participants, but higher EC activity will be associated with better neurocognitive function. In summary, this approach will allow us to elucidate several key issues, including the interaction between cannabis and the EC system, potential mechanisms that underlie these effects (lower CB2 receptor and increased FAAH expression), the assessment of EC effects on multiple biological processes implicated in HIV-mediated CNS deterioration, and the relationship between EC activity and neurocognitive performance.

描述：内源性大麻素 (EC) 系统在神经炎症和神经退行性疾病的发病机制中发挥着关键作用，包括调节促炎细胞因子、内皮激活和氧化应激。在过去的十年中，临床前研究表明，EC 系统的抗炎和神经保护特性，包括 EC CB2 受体的激活，可能具有减少 HIV 引起的中枢神经系统 (CNS) 损伤和预防艾滋病毒感染的治疗效用。 HIV 相关神经认知障碍 (HAND) 的发展。相比之下，据报道，长期接触外源性大麻会导致神经认知和功能障碍。尽管这些作用背后的神经生物学机制仍然是推测性的，但大麻暴露会降低人和小鼠的 EC 配体和受体表达，这表明 EC 系统的破坏可能在该药物的有害作用中发挥关键作用。尽管最近的研究表明，外源性大麻可以阻止精神分裂症患者上调的 EC 活动，但艾滋病毒和大麻使用对 EC 系统的单独和综合影响尚未得到表征，这代表了我们知识上的根本差距。因此，本申请将研究大麻使用、EC 功能以及与 HAND 发展有关的 HIV 相关发病机制之间的关系。我们将量化未使用大麻的 HIV 感染者和 HIV+ 参与者（每组 50 人）中两种主要内源性大麻素配体、大麻素 (AEA) 和 2-花生四烯酰甘油 (2-AG) 的脑脊液 (CSF) 和血浆水平。 d 一生中使用 5 次）、轻度使用大麻（过去一年每月 1-4 次）和重度使用大麻（过去一年每月 >10 次且符合标准）终身滥用或依赖大麻）。为了评估 HIV-EC 相互作用的潜在机制，我们还将检查单核细胞和 T 细胞中 CB2 受体的表达，以及 EC 配体失活酶脂肪酸酰胺水解酶 (FAAH) 和单酰甘油脂肪酶 (MAGL)。我们建议，作为一种补偿性保护机制，EC 配体和受体的表达在未接触过大麻的 HIV+ 参与者中会升高，但在大量使用大麻的参与者中会下降。我们还将检验以下假设：较高水平的 AEA、2-AG 和 CB2 表达与较低水平的神经炎症标志物、内皮激活和氧化应激相关。最后，我们建议，与 HIV+ 参与者不使用大麻相比，大量使用大麻会损害神经认知功能，但较高的 EC 活性将与更好的神经认知功能相关。总之，这种方法将使我们能够阐明几个关键问题，包括大麻和 EC 系统之间的相互作用、这些影响的潜在机制（降低 CB2 受体和增加 FAAH 表达）、评估 EC 对涉及的多个生物过程的影响HIV介导的中枢神经系统恶化，以及EC活动和神经认知功能之间的关系。