Sedanolide inhibits microglial activation and pyroptosis in cerebral ischemia-reperfusion injury by targeting STAT3.

Aim

This project aimed to explore whether sedanolide has an improvement effect on cerebral ischemia-reperfusion injury (CIRI) and clarify its mechanism.

Methods

CIRI models were established using rats received middle cerebral artery occlusion/reperfusion (MCAO/R) and BV2 cells treated with oxygen-glucose deprivation/regain (OGD/R). Next, pathological damage of rat brain tissues was evaluated using neurological score, rotarod test, TTC, H&E, Nissl and TUNEL staining. Immunofluorescence, western blot, ELISA and qRT-PCR were performed to detect microglial activation and pyroptosis. Cell apoptosis and viability were measured via flow cytometry and CCK-8. To explore the mechanism of sedanolide, network pharmacology was carried out and verified by rescue experiments.

Results

In MCAO/R rats, sedanolide attenuated the pathological damage of brain tissues and inhibited microglial activation and NLRP3-mediated pyroptosis, as evidenced by the decrease of neurological score, cerebral infarct volume, microglial activation markers (Iba-1, iNOS), pyroptosis-associated proteins (GSDMD-N, C-caspase-1, NLRP3, ASC) and inflammatory factors (TNF-α, IL-1β, IL-18), and the increase of M2 polarization markers (Arg-1, CD206). In OGD/R-induced BV2 cells, sedanolide enhanced cell viability and inhibited LDH release, apoptosis, microglial activation and pyroptosis. Moreover, sedanolide docked STAT3 and reduced its phosphorylation. Overexpression of STAT3 reversed the inhibitory effect of sedanolide on OGD/R-induced microglial activation and NLRP3-mediated pyroptosis in BV2 cells.

Conclusion

Sedanolide alleviated CIRI by targeting STAT3 to inhibit microglial activation and pyroptosis.