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

描述(申请人提供)：在人类和动物模型中的发现表明，酒精，类似于HIV-1，在大脑中诱导炎症过程，导致神经退化。HIV-1相关神经毒性的原因与介导酒精诱导的神经元损伤的原因类似。在之前的资助期间，我们展示了酒精引起的血脑屏障(BBB)损伤和神经元损伤，并描述了这些以前未被认识到的现象的分子机制。我们发现，在HIV-1脑炎(HIVE)的动物模型中，酒精暴露增加了神经炎症，证实了酒精滥用是HIV-1脑感染的加剧因素。减少神经炎症构成了预防HIV-1和酒精介导的神经变性的合理方法。大麻素受体2(CB2)激动剂具有强大的抗炎和神经保护作用。我们认为，CB2的激活可能通过影响单核细胞、脑内皮细胞、活化的小胶质细胞和HIV-1感染的巨噬细胞来减轻酒精和HIV-1引起的神经元功能障碍和BBB损伤。我们的研究结果证实了这一观点的相关性，即酒精和细胞因子上调了酒精和细胞因子对脑微血管内皮细胞(BMVEC)CB2表达的增强。CB2激动剂保护屏障免受炎症和酒精的伤害，阻止单核细胞通过血脑屏障的迁移，并减少激活的BMVEC中促炎因子的表达。CB2激动剂减少白细胞与脑内皮细胞的黏附，防止全身炎症小鼠血脑屏障通透性增加。基于这些观察，我们建议研究CB2激活在减轻酒精和HIV-1联合作用引起的神经炎症方面的治疗潜力。将讨论以下问题：1)CB2激动剂如何逆转酒精和病毒感染对BBB完整性的影响，并减少HIV-1感染的单核细胞在BBB上的迁移；2)CB2刺激能否缓解酒精和HIV-1感染的巨噬细胞介导的神经毒性；以及3)CB2激动剂能否在蜂窝和酒精滥用的动物模型中减少神经炎症、神经元损伤和BBB功能障碍。这项拟议工作的意义在于揭示CB2激活的抗炎潜力的新机制，该机制将改善HIV-1中枢神经系统感染和酗酒背景下的血脑屏障损伤和神经元功能障碍。 公共卫生相关性：根据2001-2年度全国酒精及相关疾病流行病学调查，超过20%的男性(18至29岁)符合可诊断的酒精使用障碍的标准：9.3%的酒精滥用和13%的酒精依赖。临床研究表明，酒精依赖对与HIV-1感染相关的认知障碍具有相加作用。目前的提案旨在了解HIV-1和酒精滥用在大脑中综合影响的机制，并提出神经保护疗法。

DESCRIPTION (provided by applicant): 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. During the previous period of funding, we demonstrated alcohol-induced impairment of the blood brain barrier (BBB) and neuronal injury and delineated molecular mechanisms of these previously unrecognized phenomena. We showed that alcohol exposure increased neuroinflammation in an animal model of HIV-1 encephalitis (HIVE), confirming that alcohol abuse is an exacerbating factor in HIV-1 brain infection. 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 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, HIVE patients 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 HIV-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. PUBLIC HEALTH RELEVANCE: According to the 2001-2 National Epidemiologic Survey on Alcohol and Related Conditions Survey, more than 20% of men (age 18 to 29) met the criteria for a diagnosable alcohol use disorder: 9.3% Alcohol Abuse and 13% Alcohol Dependence. Clinical studies indicated that alcohol dependence has an additive effect on cognitive deficits associated with HIV-1 infection. The current proposal aims to understand mechanisms of the combined effects of HIV-1 and alcohol abuse in the brain and to propose neuroprotective therapies.