Li Qi, Liu Pinyi, Zhu Xuan, Zhou Chao, Hu Yujie, Cao Shiying, Li Huiya, Zou Xinxin, Gao Shenghan, Cao Xiang, Bao Xinyu, Xu Yun, Li Jingwei
Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China.
Inflammation. 2025 Jan 3. doi: 10.1007/s10753-024-02218-9.
Microglia-mediated neuroinflammation plays a crucial role in multiple neurological diseases. We have previously found that Atglistatin, the mouse Adipose Triglyceride Lipase (ATGL) inhibitor, could promote lipid droplets (LDs) accumulation and suppress LPS-induced neuroinflammation in mouse microglia. However, Atglistatin was species-selective, which limited its use in clinical settings. Here, we found that NG-497, a previously identified human ATGL inhibitor, significantly increased LDs accumulation and inhibited LPS-induced pro-inflammatory responses in human microglia. Moreover, NG-497 also protected human neurons against neurotoxic cytokines in a humanized in vitro model of neuroinflammation. However, the anti-inflammatory capacity of NG-497 was independent of its effect on ATGL. Instead, we revealed that NG-497 alleviated microglia-mediated neuroinflammation through elevating the protein level of melatonin receptor 1A (MTNR1A). Therefore, in this study, we uncovered a novel MTNR1A-targeting compound, which exhibited anti-inflammatory and neuroprotective effect, highlighting its potential in the treatment of neuroinflammation. Moreover, the MTNRs agonist, Ramelteon, exerts comparable anti-inflammation effects with NG-497.
小胶质细胞介导的神经炎症在多种神经系统疾病中起关键作用。我们之前发现，小鼠脂肪甘油三酯脂肪酶（ATGL）抑制剂Atglistatin可促进脂滴（LDs）积累并抑制小鼠小胶质细胞中脂多糖（LPS）诱导的神经炎症。然而，Atglistatin具有物种选择性，这限制了其在临床中的应用。在此，我们发现，先前鉴定出的人源ATGL抑制剂NG-497可显著增加人小胶质细胞中脂滴的积累，并抑制LPS诱导的促炎反应。此外，在神经炎症的人源化体外模型中，NG-497还可保护人神经元免受神经毒性细胞因子的影响。然而，NG-497的抗炎能力与其对ATGL的作用无关。相反，我们发现NG-497通过提高褪黑素受体1A（MTNR1A）的蛋白水平来减轻小胶质细胞介导的神经炎症。因此，在本研究中，我们发现了一种新型的靶向MTNR1A的化合物，其具有抗炎和神经保护作用，凸显了其在神经炎症治疗中的潜力。此外，褪黑素受体激动剂雷美替胺与NG-497具有相当的抗炎效果。
