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

描述（由申请人提供）：人类和动物模型的研究结果表明，酒精与HIV-1类似，在大脑中诱导炎症过程导致神经变性。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相当。在之前的资助期间，我们证明了酒精引起的血脑屏障（BBB）损伤和神经元损伤，并描绘了这些以前未被认识到的现象的分子机制。我们发现酒精暴露增加了HIV-1脑炎（HIVE）动物模型的神经炎症，证实酒精滥用是HIV-1脑感染的加剧因素。减少神经炎症是预防HIV-1和酒精介导的神经变性的合理途径。大麻素受体2 （CB2）激动剂具有有效的抗炎和神经保护特性。我们认为CB2的激活将通过对单核细胞、脑内皮、活化的小胶质细胞和HIV-1感染的巨噬细胞的影响，减轻酒精和HIV-1引起的神经元功能障碍和血脑屏障损伤。我们的研究结果证实了这一观点的相关性，即酗酒者和HIVE患者脑内皮中CB2表达增强，酒精和细胞因子上调了原代人脑微血管内皮细胞（BMVEC）中CB2表达。CB2激动剂保护屏障免受炎症和酒精损伤，阻断单核细胞跨血脑屏障的迁移，降低激活的BMVEC中促炎因子的表达。CB2激动剂可降低全身炎症小鼠的白细胞对脑内皮的粘附，防止血脑屏障通透性增强。基于这些观察结果，我们建议研究CB2激活在减少酒精和HIV-1联合作用引起的神经炎症中的治疗潜力。以下问题将被解决：1)CB2激动剂如何逆转酒精和病毒感染对血脑屏障完整性的影响，并减少hiv -1感染的单核细胞在血脑屏障上的迁移，2)CB2刺激能否改善酒精和hiv -1感染的巨噬细胞介导的神经毒性，以及3)CB2激动剂能否减轻HIVE和酒精滥用动物模型中的神经炎症、神经元损伤和血脑屏障功能障碍。这项工作的意义在于揭示了CB2激活的抗炎潜力的新机制，这将改善HIV-1中枢神经系统感染和酒精滥用的血脑屏障损伤和神经元功能障碍。

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.