Coptisine improves LPS-induced anxiety-like behaviors by regulating the Warburg effect in microglia via PKM2

Neuroinflammation mediated by microglia is considered the primary cause and pathological process of anxiety. Abnormal glycolysis of microglia is observed during microglia activation. However, whether regulating the Warburg effect in microglia can effectively intervene anxiety and its potential mechanisms have not been elucidated. This study focused on coptisine (Cop), a natural alkaloid that regulates the glycolysis and function of microglia affecting anxiety. The effects of Cop on anxiety-like behaviors, hippocampal synaptic function, and excessive activation of microglia were assessed in lipopolysaccharide (LPS) induced mouse models of anxiety. Microglia expressing mutant pyruvate kinase isoform M2 (PKM2) were used to further investigate the molecular mechanism by which Cop regulates the phenotype of microglia. neuroinflammatory is emerging Further research revealed that Cop attaches to the amino acid residue phenylalanine 26 of PKM2, shifting the dynamic equilibrium of PKM2 towards tetramers, and enhancing its pyruvate kinase activity. This interaction prevented LPS-induced Warburg effect and inactivated PKM2/hypoxia-inducible factor-1α (HIF-1α) pathway in microglia. In conclusion, Cop attenuates anxiety by regulating the Warburg effect in microglia. Our work revealed the role of PKM2/(HIF-1α) pathway in anxiety for the first time. Importantly, the molecular mechanism by which Cop ameliorates anxiety-like behaviors is through modulation of the dimeric/tetrameric form of PKM2, indicating the usefulness of PKM2 as a key potential target for the treatment of anxiety.