NG-497 Alleviates Microglia-Mediated Neuroinflammation in a MTNR1A-Dependent Manner

  • Inflammation. 2025 Jan 3. doi: 10.1007/s10753-024-02218-9.
Qi Li  #  1  2 ,  Pinyi Liu  #  1  2 ,  Xuan Zhu  1  2 ,  Chao Zhou  1  2 ,  Yujie Hu  1  2 ,  Shiying Cao  1  2 ,  Huiya Li  1  2 ,  Xinxin Zou  1  2 ,  Shenghan Gao  1  2 ,  Xiang Cao  1  2 ,  Xinyu Bao  1  2 ,  Yun Xu  3  4  5  6 ,  Jingwei Li  7  8  9  10
Affiliations
  • 1. Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2. State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China.
  • 3. Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • 4. State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China. [email protected].
  • 5. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China. [email protected].
  • 6. Nanjing Neurology Clinical Medical Center, Nanjing, China. [email protected].
  • 7. Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • 8. State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China. [email protected].
  • 9. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China. [email protected].
  • 10. Nanjing Neurology Clinical Medical Center, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 39751706 DOI: 10.1007/s10753-024-02218-9
Abstract

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.

Keywords
ATGL; MTNR1A; Microglia; NG-497; Neuroinflammation.
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