Ligustilide ameliorates cerebral ischemia-reperfusion injury by inhibiting NLRP3 inflammasome-dependent pyroptosis through enhancing Nrf2 signaling

Pyroptosis is a type of proinflammatory programmed cell death, that closely related to the progress of cerebral ischemia / reperfusion injury (CIRI), and NLRP3 inflammasome is the most classic pathway mediating pyroptosis. Ligustilide (LIG) is a natural compound derived from the traditional Chinese herb chuanxiong hort and angelica sinensis which can penetrate the blood-brain barrier and has a good neuroprotective effect. However, it remains unclear whether LIG could alleviate CIRI by inhibiting pyroptosis. Here, the neuroprotective effect of LIG was verified by reducing NLRP3-mediated pyroptosis, and further exploring whether the inhibition of LIG on pyroptosis was related to Nuclear factor-erythropoietin 2-related factor 2(Nrf2)activation. The results showed that LIG can reduce the injury of brain tissue after ischemia, as well as NLRP3 inflammasome-mediated pyroptosis and neuroinflammation response after MCAO/R in rats. Mechanistically, the effect of LIG on Nrf2 was detected by molecular docking, protein levels and immunofluorescence analysis. We found that LIG promoted the Nrf2 expression and reduced the production of mitochondrial ROS (mtROS), and than inhibited NLRP3 inflammasome-mediated pyroptosis. Particularly revealing was that ML385, the inhibitor of Nrf2, partly blocked the above effects of LIG. All these findings suggest that LIG may ameliorate CIRI through inhibiting NLRP3 inflammasome-mediated pyroptosis dependent on Nrf2 signaling.