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

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.