CNS injury caused by HIV-1 and alcohol: Protective effects of CB2 activation

HIV-1 和酒精引起的中枢神经系统损伤：CB2 激活的保护作用

• 批准号: 9062366
• 负责人: Yuri Persidsky
• 金额: $ 37.04万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062366
• 关键词: 3-nitrotyrosine; Acetaldehyde; Address; Adhesions; Agonist; Alcohol abuse; Alcohol dependence; Alcohols; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arachidonate 5-Lipoxygenase; Astrocytes; Attenuated; Blood; Blood - brain barrier anatomy; Brain; CNR2 gene; Cell Communication; Cells; Central Nervous System Infections; Chronic; Coculture Techniques; Cognitive deficits; Data; Data Set; Down-Regulation; Elements; Encephalitis; Endothelial Cells; Endothelium; Ethanol Metabolism; Factor Analysis; Family member; Functional disorder; Funding; Glutamates; Goals; Grant; HIV; HIV-1; Human; Image; Immune response; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Instruction; Investigation; Janus kinase; Lead; Leukocytes; Link; MAPK11 gene; MAPK3 gene; MAPK8 gene; Mediating; Messenger RNA; Metalloproteases; Microglia; Modeling; Modification; Mononuclear; Mus; NADP; Nerve Degeneration; Neuraxis; Neurocognitive; Neuronal Dysfunction; Neuronal Injury; Neurons; Neurotoxins; Nitric Oxide; Oxidative Stress; Patients; Pericytes; Permeability; Phenotype; Phosphotransferases; Physiological; Prevention approach; Preventive; Process; Production; Property; Proteins; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Societies; Testing; Therapeutic; Tight Junctions; Toxic effect; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; Work; Xanthine Oxidase; alcohol effect; alcohol exposure; antiretroviral therapy; attenuation; base; brain endothelial cell; central nervous system injury; cytokine; in vivo; inducible gene expression; macrophage; migration; monocyte; neurocognitive disorder; neuroinflammation; neurotoxic; neurotoxicity; novel; oxidative damage; prevent; problem drinker; protective effect; protein degradation; protein expression; stem; two-photon

Findings in humans and animal models suggest that alcohol, similar to HIV-1, induces inflammatory processes in the brain leading to neurodegeneration. The causes of HIV-1-associated neurotoxicity are comparable to those mediating alcohol-induced neuronal injury. Diminution of neuroinflammation constitutes a logical approach for prevention of HIV-1 and alcohol mediated neurodegeneration. Agonists of cannabinoid receptor 2 (CB2) possess potent anti-inflammatory and neuroprotective properties. We propose that CB2 activation will attenuate neuronal dysfunction and blood brain barrier (BBB) injury caused by alcohol and HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Relevance of this idea is confirmed by our findings of augmented CB2 expression on brain endothelium in alcoholics, patients HIV-1 encephalitis and up-regulated CB2 expression in primary human brain microvascular endothelial cells (BMVEC) by alcohol and cytokines. CB2 agonists protected the barrier against inflammatory and alcohol insults, blocked monocyte migration across BBB and decreased expression of pro-inflammatory factors in activated BMVEC. CB2 agonist decreased leukocyte adhesion to brain endothelium and prevented enhanced BBB permeability in mice with systemic inflammation. Based on these observations, we propose to investigate the therapeutic potential of CB2 activation in diminution of neuroinflammation caused by the combined effects of alcohol and HlV-1. The following questions will be addressed: 1) How do CB2 agonists reverse the effects of alcohol and virus infection on BBB integrity and diminish migration of HIV-1-infected monocytes across the BBB, 2) Can CB2 stimulation ameliorate alcohol and HIV-1-infected macrophage-mediated neurotoxicity, and 3) Can CB2 agonists diminish neuroinflammation, neuronal injury,and BBB dysfunction in an animal model of HIVE and alcohol abuse. The significance of the proposed work is to uncover novel mechanisms underlying the anti-inflammatory potential of CB2 activation that will ameliorate BBB impairment and neuronal dysfunction in the setting of HIV-1 CNS infection and alcohol abuse. RELEVANCE (See instructions): Studies indicated that alcohol dependence has an additive effect on cognitive deficits associated with HIV-1 infection. Current proposal aims to understand the combined effects of HIV-1 and alcohol in the brain and to propose neuroprotective therapies (namely, activation of cannabinoid type 2 receptors).

人类和动物模型的发现表明，类似于HIV-1的酒精会诱发炎症 大脑的过程导致神经变性。 HIV-1相关神经毒性的原因是 与介导酒精诱导的神经元损伤的人相媲美。神经炎症的减少构成 预防HIV-1和酒精介导的神经退行性的逻辑方法。激动剂 大麻素受体2（CB2）具有有效的抗炎和神经保护特性。我们建议 CB2激活会减弱由神经元功能障碍和血液脑屏障（BBB）损伤 酒精和HIV-1通过对单核细胞，脑内皮，活化的小胶质细胞和HIV-1感染的影响 巨噬细胞。我们在大脑上表达增强的CB2表达的发现证实了这一想法的相关性 酗酒者的内皮，患者HIV-1脑炎和原代人的CB2表达上调 酒精和细胞因子的脑微血管内皮细胞（BMVEC）。 CB2激动剂保护屏障 反对炎症和酒精侮辱，单核细胞迁移遍布BBB并减少 激活的BMVEC中促炎因子的表达。 CB2激动剂降低了白细胞粘附于 脑内皮并防止了全身性炎症的小鼠的BBB渗透性增强。基于 这些观察结果，我们建议研究CB2激活在减少中的治疗潜力 通过酒精和HLV-1的综合作用引起的神经炎症。以下问题将是 发表：1）CB2激动剂如何扭转酒精和病毒感染对BBB完整性和 HIV-1感染的单核细胞在BBB上的迁移减少，2）CB2刺激可以缓解酒精 HIV-1感染的巨噬细胞介导的神经毒性，3）CB2激动剂会减少 在蜂巢和酗酒的动物模型中，神经炎症，神经元损伤和BBB功能障碍。 拟议的工作的意义是发现抗炎作用的新型机制 CB2激活的潜力将改善BBB损伤和神经元功能障碍 HIV-1 CNS感染和酗酒。 相关性（请参阅说明）： 研究表明，酒精依赖性对与HIV-1相关的认知缺陷具有加性作用 感染。当前的建议旨在了解大脑中HIV-1和酒精的综合作用以及 提出的神经保护疗法（即大麻素2受体的激活）。