Evodiamine inhibits NLRP3 inflammasome-mediated microglial pyroptosis and promotes remyelination via SLC2A4-regulated autophagy.

BACKGROUND

Activation of the NLRP3 inflammasome triggers pyroptosis, a pro-inflammatory type of cell death, in multiple sclerosis (MS). Evodiamine (EVO) possesses anti-inflammatory and neuroprotective properties; however, its potential molecular and signaling pathways in MS remain to be elucidated. This study aimed to explore the therapeutic potential of EVO for remyelination in MS and elucidated its underlying mechanisms.

METHODS

We utilized cuprizon (CPZ)/experimental autoimmune encephalomyelitis (EAE)-induced demyelinated mice and lipopolysaccharide+adenosine triphosphate (LPS+ATP)-induced pyroptosis of BV2 cells to investigate the potential of EVO in MS treatment. Various analyses were conducted, including rotarod fatigue test, RNA sequence, luxol fast blue, molecular docking, SPR, immunoblotting, qRT-PCR, immunofluorescence, and transmission electron microscopy, to analysis the targets and signaling pathways involved in EVO treatment.

RESULTS

EVO emerged as a promising remyelination agent in the CPZ/EAE demyelination models, acting through SLC2A4. Regarding its mechanism, EVO inhibited NLRP3 inflammasome-mediated microglial pyroptosis through SLC2A4 regulation of autophagy during demyelinating disease, but this change was reversed by SLC2A4 inhibitor PGF2α in vivo. Additionally, EVO inhibited LPS+ATP-induced pyroptosis of BV2 cells by preventing NLRP3 inflammasome activity and cleavage of the pyroptosis executive protein gasdermin D. It also promoted autophagy and inhibited NLRP3 inflammasome-mediated pyroptosis in BV2 cells via SLC2A4. Furthermore, an autophagy inhibitor 3-methyladenine reversed the inhibitory effect of EVO on NLRP3 inflammasome-mediated pyroptosis in BV2 cells.

CONCLUSION

The present study demonstrated that EVO inhibits NLRP3 inflammasome-mediated microglial pyroptosis and promotes remyelination via SLC2A4-regulated autophagy during demyelinating disease, which suggests EVO as a promising drug candidate for the treatment of MS.