In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND). Endocannabinoids (eCBs) elicit neuroprotective and anti-inflammatory actions in several central nervous system (CNS) disease models, but their effects in HAND remain unknown. HIV-1 does not infect neurons, but produces viral toxins, such as transactivator of transcription (Tat), that disrupt neuronal calcium equilibrium and give rise to synaptodendritic injuries and cell death, the former being highly correlated with HAND. Consequently, we tested whether the eCBs N-arachidonoylethanolamine (anandamide/AEA) and 2-arachidonoyl-glycerol (2-AG) offer neuroprotective actions in a neuronal culture model. Specifically, we examined the neuroprotective actions of these eCBs on Tat excitotoxicity in primary cultures of prefrontal cortex neurons (PFC), and whether cannabinoid receptors mediate this neuroprotection. Tat-induced excitotoxicity was reflected by increased intracellular calcium levels, synaptodendritic damage, neuronal excitability, and neuronal death. Further, upregulation of cannabinoid 1 receptor (CB1R) protein levels was noted in the presence of HIV-1 Tat. The direct application of AEA and 2-AG reduced excitotoxic levels of intracellular calcium and promoted neuronal survival following Tat exposure, which was prevented by the CB1R antagonist rimonabant, but not by the CB2R antagonist AM630. Overall, our findings indicate that eCBs protect PFC neurons from Tat excitotoxicity in vitro via a CB1R-related mechanism. Thus, the eCB system possesses promising targets for treatment of neurodegenerative disorders associated with HIV-1 infection.

中文翻译：

---

内源性大麻素在由HIV-1 Tat蛋白诱导的神经元损伤模型中发挥CB1受体介导的神经保护作用。

在联合抗逆转录病毒疗法（cART）时代，人类免疫缺陷病毒1型（HIV-1）被认为是专门针对大脑并引起HIV-1相关神经认知障碍（HAND）的慢性疾病。内源性大麻素（eCBs）在几种中枢神经系统（CNS）疾病模型中引起神经保护和抗炎作用，但它们在HAND中的作用仍未知。HIV-1不会感染神经元，但会产生病毒毒素，例如转录反式激活因子（Tat），破坏神经元钙的平衡并引起突触树突损伤和细胞死亡，前者与HAND高度相关。因此，我们测试了eCBs N-花生四烯酸乙醇胺（anandamide / AEA）和2-花生四烯酰甘油（2-AG）在神经元培养模型中是否具有神经保护作用。具体来说，我们检查了这些eCB对前额叶皮层神经元（PFC）原代培养中Tat兴奋性毒性的神经保护作用，以及大麻素受体是否介导这种神经保护作用。Tat引起的兴奋性毒性通过细胞内钙水平升高，突触树突状损害，神经元兴奋性和神经元死亡反映出来。此外，在存在HIV-1 Tat的情况下注意到了大麻素1受体（CB1R）蛋白水平的上调。AEA和2-AG的直接应用降低了Tat暴露后细胞内钙的兴奋性毒性水平，并促进了神经元存活，这被CB1R拮抗剂利莫那班阻止，但未被CB2R拮抗剂AM630阻止。总体而言，我们的发现表明eCBs通过CB1R相关机制在体外保护PFC神经元免受Tat兴奋性毒性。因此，