Study On The Mechanism Of Vinpocetine Inhibiting NLRP3 Inflammasome To Alleviate Ischemia-reperfusion Injury In Mice

Ischemic stroke is one of the leading causes of severe disability and death worldwide,which brings a significant burden to individuals and society.Inflammation is an important mechanism of nerve injury in the pathological process of ischemic stroke.NLRP3 inflammasome is an intracellular pattern recognition receptor composed of a polyprotein complex,which participates in mediating a series of inflammatory responses and is considered a potential target for ischemic stroke treatment.Vinpocetine,a derivative of vincamine,has been widely used in the prevention and treatment of ischemic stroke.However,the therapeutic mechanism of vinpocetine is not very clear,and its effect on NLRP3 inflammasome remains to be determined.In this study,we used the mouse model of transient middle cerebral artery occlusion(tMCAO)to simulate the occurrence of ischemic stroke.Different doses of vinpocetine(5,10,15mg/kg/d)were injected intraperitoneally for 3 days after ischemia-reperfusion in mice.The effects of these doses of vinpocetine on infarct volume and behavior after ischemia-reperfusion in mice were observed by TTC staining and modified neurological severity score scale,and the optimal dose was determined according to the results.Based on this optimal dose,we observed the effects of vinpocetine on the peri-infarct neuronal apoptosis,the expression of apoptosis-related proteins(Bcl-2,Bax,and Cleaved Caspase-3),the proliferation of microglia,and the expression of NLRP3 inflammasome-related genes(NLRP3,ASC,Caspase-1,IL-1β,IL-18).Besides,we compared the effects of vinpocetine and MCC950,a specific inhibitor of the NLRP3 inflammasome,on the expression of NLRP3 and downstream related proteins.Our results show that vinpocetine can effectively reduce the infarct volume,promote the recovery of behavioral function in stroke mice,and the maximal beneficial effects were observed at the dose of 10 mg/kg/d.Vinpocetine can effectively inhibit the apoptosis of peri-infarct neurons,promote the expression of Bcl-2,inhibit the expression of Bax and Cleaved Caspase-3,and reduce the proliferation of peri-infarct microglia.In addition,vinpocetine,like MCC950,can reduce the expression of NLRP3 and downstream ASC,Caspase-1,IL-1 β,IL-18.Therefore,vinpocetine can effectively alleviate the ischemia-reperfusion injury in mice,and the inhibition of NLRP3 inflammasome may be an important therapeutic mechanism of vinpocetine.