Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Front Immunol. 2024 May 21;15:1374301. doi: 10.3389/fimmu.2024.1374301. eCollection 2024.
Human immunodeficiency virus (HIV) affects nearly 40 million people globally, with roughly 80% of all people living with HIV receiving antiretroviral therapy. Antiretroviral treatment suppresses viral load in peripheral tissues but does not effectively penetrate the blood-brain barrier. Thus, viral reservoirs persist in the central nervous system and continue to produce low levels of inflammatory factors and early viral proteins, including the transactivator of transcription (Tat). HIV Tat is known to contribute to chronic neuroinflammation and synaptodendritic damage, which is associated with the development of cognitive, motor, and/or mood problems, collectively known as HIV-associated neurocognitive disorders (HAND). Cannabinoid anti-inflammatory effects are well documented, but therapeutic utility of cannabis remains limited due to its psychotropic effects, including alterations within brain regions encoding reward processing and motivation, such as the nucleus accumbens. Alternatively, inhibiting monoacylglycerol lipase (MAGL) has demonstrated therapeutic potential through interactions with the endocannabinoid system.
The present study utilized a reward-related operant behavioral task to quantify motivated behavior in female Tat transgenic mice treated with vehicle or MAGL inhibitor MJN110 (1 mg/kg). Brain tissue was collected to assess dendritic injury and neuroinflammatory profiles, including dendritic microtubule-associated protein (MAP2ab) intensity, microglia density, microglia morphology, astrocyte density, astrocytic interleukin-1ß (IL-1ß) colocalization, and various lipid mediators.
No significant behavioral differences were observed; however, MJN110 protected against Tat-induced dendritic injury by significantly upregulating MAP2ab intensity in the nucleus accumbens and in the infralimbic cortex of Tat(+) mice. No or only minor effects were noted for Iba-1 microglia density and/or microglia morphology. Further, Tat increased GFAP astrocyte density in the infralimbic cortex and GFAP astrocytic IL-1ß colocalization in the nucleus accumbens, with MJN110 significantly reducing these measures in Tat(+) subjects. Lastly, selected HETE-related inflammatory lipid mediators in the striatum were downregulated by chronic MJN110 treatment.
These findings demonstrate anti-inflammatory and neuroprotective properties of MJN110 without cannabimimetic behavioral effects and suggest a promising alternative to cannabis for managing neuroinflammation.
人类免疫缺陷病毒（HIV）在全球范围内影响着近 4000 万人，大约 80%的 HIV 感染者接受抗逆转录病毒治疗。抗逆转录病毒治疗可以抑制外周组织中的病毒载量，但不能有效地穿透血脑屏障。因此，病毒库仍然存在于中枢神经系统中，并继续产生低水平的炎症因子和早期病毒蛋白，包括转录激活因子（Tat）。已知 HIV Tat 会导致慢性神经炎症和突触树突损伤，这与认知、运动和/或情绪问题的发展有关，统称为 HIV 相关神经认知障碍（HAND）。大麻素的抗炎作用已得到充分证实，但由于其精神作用，大麻的治疗用途仍然有限，包括改变大脑中编码奖励处理和动机的区域，如伏隔核。另一方面，通过与内源性大麻素系统相互作用，抑制单酰基甘油脂肪酶（MAGL）已显示出治疗潜力。
本研究利用与奖励相关的操作性行为任务，定量分析了接受 vehicle 或 MAGL 抑制剂 MJN110（1mg/kg）治疗的雌性 Tat 转基因小鼠的动机行为。收集脑组织以评估树突损伤和神经炎症谱，包括树突微管相关蛋白（MAP2ab）强度、小胶质细胞密度、小胶质细胞形态、星形胶质细胞密度、星形胶质细胞白细胞介素-1β（IL-1β）共定位以及各种脂质介质。
未观察到明显的行为差异；然而，MJN110 可通过显著上调 Tat(+) 小鼠伏隔核和边缘下皮层中的 MAP2ab 强度，来预防 Tat 诱导的树突损伤。Iba-1 小胶质细胞密度和/或小胶质细胞形态几乎没有影响或只有轻微影响。此外，Tat 增加了边缘下皮层中的 GFAP 星形胶质细胞密度和伏隔核中的 GFAP 星形胶质细胞白细胞介素-1β共定位，而 MJN110 可显著降低 Tat(+) 受试者的这些指标。最后，纹状体中的某些 HETE 相关炎症脂质介质在慢性 MJN110 治疗后下调。
这些发现表明，MJN110 具有抗炎和神经保护作用，而无大麻样行为作用，并为管理神经炎症提供了一种有希望的大麻替代疗法。
