Cai Yu, Yang Lu, Callen Shannon, Buch Shilpa
Department of Pharmacology &, Experimental Neuroscience, University of Nebraska, Omaha, Nebraska, USA.
Curr HIV Res. 2016;14(5):412-416. doi: 10.2174/1570162x14666160324125158.
While the advancement of highly active antiretroviral therapy (HAART) has transformed the course of HIV/AIDS from a death sentence to a manageable chronic condition, the prevalence of a constellation of neurological disorders collectively termed as HIV-associated neurocognitive disorders (HAND) continues to persist in these patients. HAND is characterized by cognitive dysfunction, depression, impaired memory and/or deficits in motor skills. The underlying factors leading to HAND have been the subject of extensive research and are thought to be associated with HIV infection in the CNS combined with robust immune activation of resident cells of the CNS. In addition, there is a strong correlation between chronic substance abuse and the manifestation of HAND. Among the various commonly abused drugs, cocaine has been extensively studied for its ability to exacerbate the neuropathogenesis of HAND. Ample evidence suggests that cocaine not only facilitates viral replication in macrophages and microglia, but also inflicts deleterious effects on various other cells of the CNS, thereby contributing to the potentiation of HAND. Cocaine has been shown to enhance the permeability of the blood-brain barrier (BBB) through various mechanisms including direct pro-apoptotic effects on brain endothelial cells, systemic induction of inflammatory factors which have been demonstrated to down-regulate tight junction proteins and via up-regulation of several endothelial adhesion molecules leading to accelerated breach of the BBB and increased influx of HIV-infected leukocytes into the CNS. Cocaine also enhances viral replication in CNS astrocytes and promotes astrogliosis via astrocyte activation and proliferation. Furthermore, cocaine also exacerbates neuroinflammatory responses by mediating microglial activation and migration. In addition to cellular injury mediated by inflammatory responses, cocaine also directly affects the brain reward system by disrupting the homeostasis of neurotransmitters such as dopamine and acetylcholine and works synergistically with viral proteins such as tat and gp120 to promote neuronal injury.
This review highlights previous studies in the field on the role of cocaine in the progression of HAND and gives an overview of the major signaling pathways in the CNS that are involved in this process.
虽然高效抗逆转录病毒疗法（HAART）的进步已将艾滋病毒/艾滋病的病程从死刑转变为可控制的慢性病，但在这些患者中，统称为艾滋病毒相关神经认知障碍（HAND）的一系列神经疾病的患病率仍然居高不下。HAND的特征是认知功能障碍、抑郁、记忆受损和/或运动技能缺陷。导致HAND的潜在因素一直是广泛研究的主题，被认为与中枢神经系统中的艾滋病毒感染以及中枢神经系统常驻细胞的强烈免疫激活有关。此外，慢性药物滥用与HAND的表现之间存在很强的相关性。在各种常见的滥用药物中，可卡因因其加剧HAND神经发病机制的能力而受到广泛研究。大量证据表明，可卡因不仅促进巨噬细胞和小胶质细胞中的病毒复制，还对中枢神经系统的各种其他细胞造成有害影响，从而导致HAND的加剧。可卡因已被证明通过多种机制增强血脑屏障（BBB）的通透性，包括对脑内皮细胞的直接促凋亡作用、全身性诱导炎症因子，这些炎症因子已被证明可下调紧密连接蛋白，以及通过上调几种内皮粘附分子导致血脑屏障加速破坏和艾滋病毒感染的白细胞向中枢神经系统的流入增加。可卡因还增强中枢神经系统星形胶质细胞中的病毒复制，并通过星形胶质细胞激活和增殖促进星形胶质细胞增生。此外，可卡因还通过介导小胶质细胞激活和迁移加剧神经炎症反应。除了炎症反应介导的细胞损伤外，可卡因还通过破坏多巴胺和乙酰胆碱等神经递质的稳态直接影响大脑奖赏系统，并与tat和gp120等病毒蛋白协同作用，促进神经元损伤。
本综述强调了该领域先前关于可卡因在HAND进展中的作用的研究，并概述了中枢神经系统中参与这一过程的主要信号通路。
