Endocannabinoids, Cannabis, and Neurocognitive Deficits in HIV

产品说明：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起着关键作用，包括调节促炎细胞因子、内皮活化和氧化应激。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 CB 2受体的激活，可能在减少HIV诱导的中枢神经系统（CNS）损伤和预防HIV相关神经认知障碍（HAND）的发展方面具有治疗效用。相比之下，据报告，外源性大麻的使用在长期接触后会引起神经认知和功能障碍。虽然这些影响的神经生物学机制仍然是推测性的，但大麻暴露降低了人类和小鼠的EC配体和受体表达，这表明EC系统的破坏可能在这种药物的有害作用中发挥关键作用。而 最近的研究表明，外源性大麻可以阻断精神分裂症患者的EC活性上调，但艾滋病毒和大麻使用对EC系统的单独和联合影响尚未得到表征，这代表了我们知识的根本差距。因此，本申请将研究大麻的使用，EC功能和HIV相关的发病机制之间的关系牵连的发展手。我们将定量HIV-和HIV+参与者的脑脊液（CSF）和血浆中两种主要内源性大麻素配体，花生四烯酸酰胺（AEA）和2-花生四烯酸甘油（2-AG）的水平（每组50例），未使用大麻（d一生中5次），大麻轻度使用（过去一年每月1-4次）和大量使用大麻（过去一年每月>10次，符合终生滥用大麻或依赖大麻的标准）。为了评估HIV-EC相互作用的潜在机制，我们还将检查单核细胞和T细胞中CB 2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，EC配体和受体的表达将在大麻初治的HIV+参与者中升高，作为一种补偿性保护机制，但在大量使用大麻的参与者中下降。我们还将检验以下假设：较高水平的AEA、2-AG和CB 2表达将与较低水平的神经炎症标志物、内皮活化和氧化应激相关。最后，我们提出，与没有使用大麻的HIV+参与者相比，大量使用大麻会损害神经认知功能，但更高的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CB 2受体和增加FAAH表达），EC对HIV介导的CNS恶化中涉及的多种生物过程的影响的评估，以及EC活性和神经认知性能之间的关系。

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.