Maresin1 alleviates neuroinflammation by inhibiting caspase-3/ GSDME-mediated pyroptosis in mice cerebral ischemia-reperfusion model

Objective: To explore the mechanism of Maresin1 in reducing cerebral ischemia-reperfusion injury.

Materials and methods: Male C57BL/6 mice were randomly divided (n = 5 in each group), and focal middle cerebral artery occlusion (MCAO) model was used to simulate cerebral ischemia/reperfusion injury. TTC and the Longa score were used to detect the degree of neurological deficits. Western blot was used to detect the expression levels of GSDME, GSDME-N, Caspase-3 and cleaved Caspase-3 in cerebral ischemic penumbra tissue, and immunofluorescence was used to detect the expression levels of GSDME-N. The mRNA expression levels of GSDME and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) were detected by RT-PCR.

Results: Compared with sham group, GSDME mRNA levels in MCAO group were significantly increased at 12 h and 24 h after reperfusion, and GSDME and GSDME-N significantly increased at 6-48 h after reperfusion. Compared with sham group, the percentage of infarct size, the Longa score, the mRNA expression levels of IL-1β, IL-6 and TNF-α, and GSDME, GSDME-N, Caspase-3 and cleaved Caspase-3 in MCAO group was significantly increased. Then, the percentage of infarct size and the Longa score significantly decreased after MaR1 administration, the mRNA expression levels of IL-1β and IL-6 downregulated, and GSDME, GSDME-N, Caspase-3 and cleaved Caspase-3 were also reduced. After administration of Z-DEVD-FMK(ZDF), the expression of Caspase-3, cleaved Caspase-3 and GSDME-N was decreased, which in MCAO+MaR1+ZDF group was not statistically significant compared with MCAO+ ZDF group.

Conclusion: Maresin1 alleviates cerebral ischemia/reperfusion injury by inhibiting Pyroptosis mediated by Caspase-3/GSDME pathway and alleviating neuroinflammation.

Caspase-3; Cerebral ischemia-reperfusion injury; GSDME; Inflammation; Pyroptosis.