Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA; Department of Microbiology and Immunology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
Brain Res. 2019 Nov 15;1723:146409. doi: 10.1016/j.brainres.2019.146409. Epub 2019 Aug 26.
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite effective antiretroviral therapies (ART). Evidence suggests that modern HAND is driven by subtle synaptodendritic damage in select brain regions, as ART-treated patients do not display overt neuronal death in postmortem brain studies. HAND symptoms are also aggravated by drug abuse, particularly with injection opioids. Opioid use produces region-specific synaptodendritic damage in similar brain regions, suggesting a convergent mechanism that may enhance HAND progression in opioid-using patients. Importantly, studies indicate that synaptodendritic damage and cognitive impairment in HAND may be reversible. Activation of the homeostatic chemokine receptor CXCR4 by its natural ligand CXCL12 positively regulates neuronal survival and dendritic spine density in cortical neurons, reducing functional deficits. However, the molecular mechanisms that underlie CXCR4, as well as opioid-mediated regulation of dendritic spines are not completely defined. Here, we will consolidate studies that describe the region-specific synaptodendritic damage in the cerebral cortex of patients and animal models of HAND, describe the pathways by which opioids may contribute to cortical synaptodendritic damage, and discuss the prospects of using the CXCR4 signaling pathway to identify new approaches to reverse dendritic spine deficits. Additionally, we will discuss novel research questions that have emerged from recent studies of CXCR4 and µ-opioid actions in the cortex. Understanding the pathways that underlie synaptodendritic damage and rescue are necessary for developing novel, effective therapeutics for this growing patient population.
人类免疫缺陷病毒 (HIV) 相关的神经认知障碍 (HAND) 尽管有有效的抗逆转录病毒疗法 (ART)，但仍持续存在。有证据表明，现代 HAND 是由特定脑区的细微突触树突损伤驱动的，因为在接受 ART 治疗的患者的尸检大脑研究中并未显示出明显的神经元死亡。HAND 症状也因药物滥用而加重，尤其是注射类阿片类药物。阿片类药物的使用会导致特定区域的突触树突损伤，这表明存在一种趋同机制，可能会加剧使用阿片类药物的患者 HAND 的进展。重要的是，研究表明 HAND 中的突触树突损伤和认知障碍可能是可逆的。其天然配体 CXCL12 对同源化学趋化因子受体 CXCR4 的激活正向调节皮质神经元的存活和树突棘密度，从而减少功能缺陷。然而，CXCR4 以及阿片类药物介导的树突棘调节的分子机制尚未完全确定。在这里，我们将整合描述 HAND 患者和动物模型大脑皮质中特定区域的突触树突损伤的研究，描述阿片类药物可能导致皮质突触树突损伤的途径，并讨论利用 CXCR4 信号通路来识别新方法以逆转树突棘缺陷的前景。此外，我们将讨论从最近关于 CXCR4 和 µ 阿片类药物在大脑中的作用的研究中出现的新的研究问题。了解导致突触树突损伤和挽救的途径对于为这一不断增长的患者群体开发新的、有效的治疗方法是必要的。
