Methyl isoeugenol suppresses NLRP3 inflammasome-mediated pyroptosis via activation of Nrf2/NQO1/HO-1 signaling in cerebral ischemia-reperfusion injury

Microglial neuroinflammation is considered to be a vital injury factor aggravating ischemia-reperfusion (I/R) injury on the progression of cerebral ischemic stroke. Mounting evidences have verified the effect of Pyroptosis mediated by NLRP3 inflammasome on modulating microglial phenotype, and maintaining the microglial M1/M2 phenotype balance could be a novel target to ameliorate cerebral I/R injury. Herein, we focused on the anti-neuroinflammatory effect of methyl isoeugenol, a bioactive compound isolated from Acorus tatarinowii Schott, on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated NLRP3 inflammasome in vivo or in vitro. The results showed that methyl isoeugenol reduced cerebral infarct volume, modulated microglia M1/M2 phenotypes, and protected against NLRP3 inflammasome-primed Pyroptosis. Mechanistically, methyl isoeugenol increased the nuclear translocation of Nrf2 and decreased that of NF-κB, and consequently, upregulated cellular Antioxidants (HO-1 and NQO1), with the increased expression of antioxidant Enzymes SOD and the decreased expression of lipid peroxidation MDA. These findings suggest that Nrf2 may serve as a vital target for the protective effect of methyl isoeugenol, making methyl isoeugenol as a promising anti-neuroinflammatory agent for NLRP3 inflammasome mediated microglial neuroinflammation in I/R injury.