Metformin attenuates early brain injury after subarachnoid hemorrhage by inhibiting neuronal apoptosis through Sirt1
Objective To determine whether metformin(Met)can attenuate early brain injury(EBI)after subarachnoid hemorrhage(SAH)by inhibiting neuronal apoptosis through Sirt1.Methods Mice were randomly divided into sham operation group,SAH 24 h group,SAH+Met 24 h group,SAH 48 h group,SAH+Met 48 h group,SAH 72 h group and SAH+Met 72 h group(n=10 per group).The mouse model of SAH was established by blood injection of the anterior cisterna optic chiasma.The modified Garcia score,brain water content,blood-brain barrier damage assessment and Morris water maze test were performed in each group.Sirt1,Bcl-2,Bax,Cleaved Caspase-3 protein levels were detected in each group,and Tunel assay and Nissl staining were combined to determine whether Met inhibited neuronal apoptosis during EBI.Fetal rat prima-ry neuron SAH model was used in vitro and divided into control group,OxyHb group,OxyHb+Met group,OxyHb+Vehicle group and OxyHb+Met+EX527 group(n=12 per group).The protein levels of Sirt1,Bcl-2,Bax,Cleaved Caspase-3 were detected in each group,and the results of animal experiments were verified by Tunel assay.EX527 was added to inhibit Sirt1 to investigate the potential mecha-nism by which Met inhibits neuronal apoptosis.Results Compared with SAH group,neurological dysfunction was significantly improved in the SAH+Met group.Compared with SAH 48h group,Sirt1 and Bcl-2 levels in SAH+Met 48h group were significantly increased(P＜0.01),while Bax and Cleaved Caspase-3 levels were significantly decreased(P＜0.01).Tunel and Nissl staining showed that the apoptotic cells in SAH+Met group were significantly reduced(P＜0.01).In vitro experiments,compared with the OxyHb group,the levels of Sirt1 and Bcl-2 in the OxyHb+Met group were significantly in-creased(P＜0.01),and the levels of Bax and Cleaved Caspase-3 were significantly decreased(P＜0.01),and this effect was inhibited after the addition of EX527.Conclusion Met can inhibit neuronal apoptosis during the process of EBI by activating the Sirt1 path-way,improve the prognosis of SAH,and provide a new therapeutic target and treatment strategy for clinical treatment of SAH.
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