Endocannabinoids, Cannabis, and Neurocognitive Deficits in HIV

描述：内源性大麻素(EC)系统在神经炎性和神经退行性疾病的发病机制中起关键作用，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，包括激活EC CB2受体，可能在减少HIV对中枢神经系统(CNS)的损伤和防止HIV相关性神经认知障碍(HAND)的发展方面具有治疗作用。相比之下，据报道，使用外源性大麻会在长期暴露后导致神经认知和功能损害。尽管这些效应背后的神经生物学机制仍然是推测的，但大麻暴露降低了EC配体和受体在人类和小鼠中的表达，表明EC系统的破坏可能在这种药物的有害影响中发挥关键作用。而当 最近的研究表明，外源性大麻可以阻断精神分裂症患者上调的EC活性，但艾滋病毒和大麻使用对EC系统的单独和联合影响尚未确定，这是我们认识上的一个根本差距。因此，这项应用将研究大麻使用、EC功能和Hand发育过程中涉及的HIV相关发病机制之间的关系。我们将量化艾滋病毒携带者和艾滋病毒携带者(每组50人)脑脊液(CSF)和血浆中两种主要的内源性大麻素配体--花生胺(AEA)和2-花生四烯基甘油(2-AG)的水平，这些参与者没有使用大麻(一生中有5次吸食大麻)、少量吸食大麻(过去一年每月1-4次)和大量吸食大麻(在过去一年中每月10次，符合终身滥用或依赖大麻的标准)。为了评估HIV-EC相互作用的潜在机制，我们还将检测单核细胞和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)的表达。我们认为，作为一种代偿保护机制，在未吸食大麻的HIV+参与者中，EC配体和受体的表达将增加，但在大量使用大麻的参与者中，EC配体和受体的表达将下降。我们还将检验这一假设，即AEA、2-AG和CB2表达水平较高将与神经炎性标志物、内皮激活和氧化应激水平较低相关。最后，我们认为，与不使用大麻相比，在HIV+参与者中，大量使用大麻会损害神经认知能力，但更高的EC活性将与更好的神经认知功能相关。总之，这一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(CB2受体降低和FAAH表达增加)，EC对HIV介导的中枢神经系统恶化所涉及的多个生物学过程的影响的评估，以及EC活动和神经认知能力之间的关系。

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.