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

在人类和动物模型中的研究结果表明，酒精与HIV-1类似，会导致炎症 大脑中的过程会导致神经退化。HIV-1相关神经毒性的原因是 与那些介导酒精诱导的神经元损伤的作用相当。神经炎症的消退构成 预防HIV-1和酒精介导的神经变性的合理方法。血管紧张素转换酶激动剂 大麻素受体2(CB2)具有强大的抗炎和神经保护作用。我们建议 CB2激活可减轻脑神经功能障碍和血脑屏障(BBB)损伤 酒精和HIV-1对单核细胞、脑内皮细胞、激活的小胶质细胞和HIV-1感染的影响 巨噬细胞。这一想法的相关性被我们在大脑中增强的CB2表达的发现所证实 酒精、HIV-1脑炎患者血管内皮细胞和原代人类CB2表达上调 酒精和细胞因子对脑微血管内皮细胞的刺激作用。CB2激动剂保护屏障 对抗炎症和酒精侮辱，阻止单核细胞跨血脑屏障迁移，并减少 促炎症因子在活化的BMVEC中的表达。CB2激动剂降低白细胞对 并防止全身炎症小鼠血脑屏障通透性增加。基于 在这些观察中，我们建议研究CB2激活在减少 由酒精和HLV-1共同作用引起的神经炎症。以下问题将是 讨论：1)CB2激动剂如何逆转酒精和病毒感染对血脑屏障完整性和 减少HIV-1感染的单核细胞跨越血脑屏障的迁移，2)CB2刺激可以改善酒精 和HIV-1感染的巨噬细胞介导的神经毒性，以及3)CB2激动剂能否减弱 蜂房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。 这项拟议工作的意义在于揭示了抗炎的新机制。 CB2激活可能改善脑缺血后血脑屏障损害和神经元功能障碍 HIV-1中枢神经系统感染和酗酒。 相关性(请参阅说明)： 研究表明，酒精依赖对与HIV-1相关的认知障碍具有相加作用 感染。目前的提案旨在了解HIV-1和酒精在大脑中的联合影响，并 提出神经保护疗法(即激活大麻素2型受体)。

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).