Endocannabinoid-mediated neuroprotection in models of neuroAIDS in vivo

体内神经艾滋病模型中内源性大麻素介导的神经保护

• 批准号: 9906196
• 负责人: Sylvia Fitting
• 金额: $ 36.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906196
• 关键词: 2-arachidonylglycerol; AM 251; AM630; Affect; Alzheimer' s Disease; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Astrocytes; Behavior; Behavioral; Behavioral inhibition; Benzodiazepine Receptor; Brain; Brain Diseases; CNR1 gene; CNR2 gene; Cannabis; Chronic; Chronic Disease; Cognitive; Cognitive deficits; Consequences of HIV; Decision Making; Defect; Disease; Electrophysiology (science); Endocannabinoids; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Exhibits; FAAH inhibitor; Goals; HIV; HIV Envelope Protein gp120; HIV-1; HIV-associated neurocognitive disorder; High Prevalence; Imaging Techniques; Impulsivity; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injury; Investigation; Knowledge; Laboratories; Ligands; Location; Longitudinal Studies; MAGL inhibitor; Magnetic Resonance Imaging; Medial; Mediating; Modeling; Monitor; Monoacylglycerol Lipases; Morphology; Nerve Degeneration; Nervous System Trauma; Neurocognitive Deficit; Neurodegenerative Disorders; Neuroglia; Neuromodulator; Neuronal Injury; Operant Conditioning; Parkinson Disease; Pathology; Patients; Peripheral; Pharmacology; Physiological; Play; Positron-Emission Tomography; Prefrontal Cortex; Process; Property; Proteins; Role; Site; Specificity; Structure; Synapses; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Tracer; Training; Transgenic Mice; Vertebral column; anandamide; antiretroviral therapy; cognitive function; density; endocannabinoid signaling; endogenous cannabinoid system; excitotoxicity; executive function; fatty acid amide hydrolase; hippocampal pyramidal neuron; imaging study; in vivo; in vivo imaging; inflammatory marker; inhibitor/antagonist; interest; longitudinal positron emission tomography; memory consolidation; mouse model; nervous system disorder; neuroAIDS; neurocognitive disorder; neuroinflammation; neuron development; neuronal survival; neuroprotection; new therapeutic target; non-invasive imaging; pre-clinical; preclinical study; prevent; protective effect; receptor; response; rimonabant; side effect; synaptic function; synthetic cannabinoid; tat Protein; therapeutic target; tool; treatment response

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.

项目摘要/摘要 包括帕金森氏症和阿尔茨海默氏病在内的几种神经退行性疾病显示 内源性大麻素（ECB）系统的功能。在联合抗逆转录病毒疗法（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 专门针对大脑并引起艾滋病毒相关神经认知的高流行率的成分 疾病（手）。欧洲央行系统吸引了兴趣作为治疗神经退行性的目标 由于潜在的神经保护性，CBS的抗炎和神经营养特性，疾病。然而， ECB在体内的治疗使用不太可能是由于它们的分解代谢酶的快速降解。主 负责降解两个主要ECB的酶，Anandamide（AEA）和2-砷烯丙基甘油（2-- Ag），分别是：脂肪酸酰胺水解酶（FAAH）和单酰甘油脂肪酶（MAGL）。一个新的类 已经开发了这些酶的选择性抑制剂，显示出神经保护和抗炎 神经退行性疾病的临床前动物模型的影响。这些新的药品工具允许 欧洲央行信号的选择性升高，可以调查特定ECB的物理作用 以及这种精确调节的治疗潜力。本研究的目的是揭开 欧洲央行信号传导在针对HIV-1蛋白毒性的神经保护中的作用，导致行为变化为 手的结果。为了实现这一目标，我们计划使用TAT和GP120转基因（TG）小鼠， 已建立的神经辅助模型，这将使​​我们能够确定：1）ECB的神经保护作用对 使用分解代谢酶抑制，前额叶皮层（PFC）依赖性行为； 2）机制 ECB在PFC离体中的潜在保护作用； 3）慢性欧洲央行分解代谢酶的影响 使用二极化发射断层扫描（PET）成像在体内对神经炎症的抑制剂。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对 通过CB1R/CB2R介导的机制通过行为，功能和结构。在特定的目标1中，Tat TG小鼠将是 经过操作条件的GO/NO-GO任务和ECB酶抑制剂的培训将进行保护 反对TAT引起的认知功能干扰的影响，包括行为抑制和 冲动的增加。此外，相同的动物将对PFC锥体进行电生理研究 神经元在体内建立欧洲酶抑制剂对突触电流的影响。在特定的目标2中，我们 将进行行为，功能和形态成像研究，以确定ECB是否为神经保护作用 在TAT毒性中，通过CB1R/CB2R介导的机制离体。在特定的目标3中，非侵入性纵向宠物 TAT和GP120 TG小鼠中的成像研究将研究欧洲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上的作用 艾滋病可能会发现发生认知缺陷的手动和其他疾病的新型治疗靶标。