| Background:Neuroinflammation plays important role in the pathological mechanisms of early brain injury after subarachnoid hemorrhage(SAH).Metformin possesses a protective effect toward multiple diseases via inhibiting the NLRP3-induced inflammation reaction.This study aimed to explore whether metformin could improve brain injury after SAH by suppressing the NLRP3 relevant neuroinflammation and the involved mechanism.Methods:A mouse model of SAH was generated with endovascular perforation.Western blot and immunofluorescent staining were used to detect the temporal pattern of NLRP3 and p-AMPK after SAH induction.Metformin was given by intraperitoneal injection half an hour after SAH,the neurological scores,brain water content,and western blot were applied to identify the role of metformin on brain injury and NLRP3 expression following SAH.Tunel staining,Nissl staining,and FJC staining were performed to assess the effect of metformin administration on cell apoptosis and neuronal damage.After the selective AMPK inhibitor compound C was given by intracerebroventricular injection,neurological scores,brain water content,immunohistochemical staining,immunofluorescent staining,and western blot were applied to identify the role of metformin on NLRP3 associated neuroinflammation and microglial activation after S AH and the specific mechanism.Results:Metformin improved short-term neurological functions,brain edema,and neuronal injury at 24 h after S AH.Metformin enhanced the level of p-AMPK,but reduced the levels of NLRP3,cleaved caspase 1,cleaved IL-1β,and cleaved IL-18.Moreover,metformin mitigated the excessive activation of microglial cells.However,inhibition of AMPK weakened the protective effects and anti-inflammatory effects of metformin at 24 h after SAH.Conclusion:Metformin exerts its neuroprotective effects by inhibiting neuroinflammation in an AMPK-dependent manner,by modulating the production of NLRP3-associated proinflammatory factors and the activation of microglia. |
