Endocannabinoid-mediated neuroprotection in models of neuroAIDS in vivo

项目摘要/摘要 包括帕金森氏症和阿尔茨海默病在内的几种神经退行性疾病在 内源性大麻素(ECB)系统的功能。在联合抗逆转录病毒治疗(CART)的时代， 人类免疫缺陷病毒1型(HIV-1)现在被认为是一种慢性疾病，具有炎症性 专门针对大脑并导致艾滋病毒相关神经认知高发的成分 精神障碍(手)。欧洲央行系统作为治疗神经退行性变的靶点引起了人们的兴趣 由于CBS潜在的神经保护、抗炎和神经营养特性而导致的疾病。然而， ECB不太可能在体内用于治疗，因为它们被分解代谢酶迅速降解。主 负责降解两种主要ECB的酶--烷基酰胺(AEA)和2-芳香酮酰甘油(2- AG)，分别为：脂肪酸酰胺水解酶(FAAH)和单甘油脂肪酶(MAGL)。一个新的阶层 这些酶的选择性抑制剂已经被开发出来，显示出神经保护和抗炎作用。 对临床前神经退行性疾病动物模型的影响。这些新的药理工具允许 ECB信号的选择性提升，这使得能够研究特定ECB的生理行为 也揭示了这种精确调控的治疗潜力。本研究的目的是解开 ECB信号在抗HIV-1蛋白毒性导致的行为改变中的神经保护作用 这是徒手的结果。为了实现这个目标，我们计划使用TAT和gp120转基因(TG)小鼠，以及- 已建立的神经艾滋病模型，这将使我们能够确定：1)ECbs的神经保护作用 利用分解代谢酶抑制前额叶皮质(PFC)依赖的在体行为；2)机制 ECB对体外PFC的潜在保护作用；3)慢性ECB分解代谢酶的作用 用正电子发射断层扫描(PET)技术研究体内神经炎症的抑制剂。我们假设 在HIV-1蛋白TG小鼠模型中，ECB分解代谢酶抑制剂将对 行为、功能和结构通过CB1R/CB2R介导的机制。在特定的目标1中，TAT TG小鼠将被 将对操作员条件调节GO/NO-GO任务和ECB酶抑制剂进行保护测试 对TAT诱导的认知功能干扰的影响，包括减少行为抑制和 增加了冲动。此外，相同的动物将接受PFC锥体的电生理学研究 以建立ECB酶抑制剂对突触电流的影响。在具体目标2中，我们 将进行行为、功能和形态成像研究，以确定ECB是否具有神经保护作用 TAT的毒性作用是通过CB1R/CB2R介导的体外机制。在特定目标3中，无创纵向PET 在tat和gp120 tg小鼠中的成像研究将探讨ecb酶抑制剂对活性的影响。 使用示踪剂[18F]-PBR111的炎症过程。了解欧洲央行系统在神经系统中的作用 艾滋病可能为手部和其他出现认知缺陷的疾病发现新的治疗靶点。

Project Summary/Abstract Several neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases, display alterations in the function of the endocannabinoid (eCB) system. In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-associated neurocognitive disorders (HAND). The eCB system has attracted interest as a target for treatment of neurodegenerative disorders, due to the potential neuroprotective, anti-inflammatory, & neurotrophic properties of CBs. However, therapeutic use of eCBs in vivo is unlikely due to their rapid degradation by catabolic enzymes. The main enzymes responsible for degradation of two major eCBs, anandamide (AEA) and 2-arochinonoylglycerol (2- AG), are respectively: fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MAGL). A new class of selective inhibitors of those enzymes has been developed that show neuroprotective and anti-inflammatory effects in preclinical animal models of neurodegenerative diseases. These new pharmacological tools allow for selective elevation of eCB signaling, which enables investigation of physiological actions of particular eCBs as well as reveal therapeutic potential of such precise modulation. The aim of the present study is to unravel the role of the eCB signaling in neuroprotection against HIV-1 protein toxicity that results in behavioral changes as a consequence of HAND. To achieve this goal, we plan to use Tat and gp120 transgenic (tg) mice, as well- established models of neuroAIDS, that will allow us to determine: 1) the neuroprotective effects of eCBs on prefrontal cortex (PFC)-dependent behavior in vivo, with use of catabolic enzyme inhibition; 2) the mechanisms underlying protective effects of eCBs in PFC ex vivo; and 3) the effects of chronic eCB catabolic enzyme inhibitors on neuroinflammation using positron emission tomography (PET) imaging in vivo. We hypothesize that in the HIV-1 protein tg mouse models, eCB catabolic enzyme inhibitors will show protective effects on behavior, function, and structure via a CB1R/CB2R-mediated mechanism. In Specific Aim 1, Tat tg mice will be trained on the operant conditioning Go/No-Go task and eCB enzyme inhibitors will be tested for protective effects against Tat-induced interference in cognitive function, including a decrease of behavioral inhibition and increased impulsivity. Moreover, the same animals will undergo electrophysiology studies on PFC pyramidal neurons ex vivo to establish the effects of eCB enzyme inhibitors on synaptic currents. In Specific Aim 2, we will conduct behavioral, functional, and morphological imaging studies to determine if eCBs are neuroprotective in Tat toxicity via a CB1R/CB2R-mediated mechanism ex vivo. In Specific Aim 3, non-invasive longitudinal PET imaging studies in Tat and gp120 tg mice will investigate the effects of eCB enzyme inhibitors on active inflammatory processes using the tracer [18F]-PBR111. Understanding the role of the eCB system in neuro- AIDS may uncover novel therapeutic targets for HAND and other diseases in which cognitive deficits occur.