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

基本信息

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
项目类别：
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

项目摘要

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).

人类和动物模型的研究结果表明，酒精与 HIV-1 类似，会诱发炎症大脑中导致神经退行性变的过程。 HIV-1相关神经毒性的原因是与介导酒精引起的神经元损伤的那些类似。神经炎症的减少构成预防 HIV-1 和酒精介导的神经变性的合理方法。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 激活将减轻神经元功能障碍和血脑屏障 (BBB) 损伤酒精和 HIV-1 通过影响单核细胞、脑内皮、激活的小胶质细胞和 HIV-1 感染巨噬细胞。我们对大脑中 CB2 表达增强的发现证实了这一想法的相关性酗酒者、HIV-1 脑炎患者的内皮细胞和原代人类中 CB2 表达上调脑微血管内皮细胞（BMVEC）受酒精和细胞因子的影响。 CB2激动剂保护屏障对抗炎症和酒精损伤，阻止单核细胞跨 BBB 迁移并减少激活的 BMVEC 中促炎因子的表达。 CB2激动剂降低白细胞粘附脑内皮细胞并防止全身炎症小鼠的血脑屏障通透性增强。基于根据这些观察结果，我们建议研究 CB2 激活在减少由酒精和 HIV-1 联合作用引起的神经炎症。将提出以下问题解决：1) CB2 激动剂如何逆转酒精和病毒感染对 BBB 完整性和减少 HIV-1 感染的单核细胞穿过 BBB 的迁移，2) CB2 刺激可以改善酒精吗和 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 HIVE 和酒精滥用动物模型中的神经炎症、神经元损伤和 BBB 功能障碍。这项工作的意义在于揭示抗炎作用的新机制 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（参见说明）：研究表明，酒精依赖对与 HIV-1 相关的认知缺陷具有累加效应感染。目前的提案旨在了解 HIV-1 和酒精对大脑的综合影响，并提出神经保护疗法（即激活大麻素 2 型受体）。