A Comparative Study On The Neuroprotective Effects Of Glimepiride And Glibenclamide After Acute Ischemic Stroke

BackgroundCurrent pharmacotherapy for acute ischemic stroke is still largely dependent on thrombolysis by tissue plasminogen activator.It determines that glibenclamide protects against cerebral ischemic injury in both preclinical and clinical studies,presumably by blocking the de novo assembled sulfonylurea receptor 1-transient receptor potential M4(Sur1-Trpm4)channel induced by ischemia.As a weak acid,glibenclamide takes advantage of its lipophilicity to reach the acidic targeted ischemic tissues under a relatively low dose,which thus greatly lowers its hypoglycemic risk.However,the oral formulation of glibenclamide is associated with a higher rate of serious hypoglycemia than the other common oral antidiabetic medications.In addition,treatment with glibenclamide is associated with increased all-cause and cardiovascular mortality in patients with type 2 diabetes mellitus.ObjectivesHere,we tested whether glimepiride,the latest second-generation sulfonylurea with better safety,has comparable efficacy with glibenclamide and whether gene deletion of Trpm4(Trpm4-/-)exerts similar effect.MethodsWild-type(WT)and Trpm4-/-mice on C57BL/6J background were subjected to temporary middle cerebral artery occlusion(tMCAO)as were detecting cerebral blood flow with laser Dopper and motoring blood glucose with a glucometer.1.WT mice were randomized to receive glibenclamide(an initial dose of 10 μg/kg and additional doses of 1.2 μg every 8 hours),three different doses of glimepiride(10μg/kg,100 μg/kg and 1mg/kg)or vehicle after acute ischemic stroke.Neurological function,infarct volume,edema formation,the integrity of blood-brain barrier and inflammatory reaction were evaluated at 24 hours after ischemia.2.The expression of Surl and Trpm4 were detected at 24 hours after ischemia.3.tMCAO-treated Trpm4-/-mice were randomized to receive vehicle or glimepiride.Neurological function,infarct volume,edema formation and the integrity of blood-brain barrier were evaluated at 24 hours after ischemia.Results1.At 24 hours after ischemia,in tMCAO-treated WT mice,10 μg/kg and 100μg/kg glimepiride had comparable efficacy with glibenclamide in dicreasing Longa score,increasing grip test score,reducing infarct volume,mitigating brain edema,lessening extravasation of Evans blue dye and IgG,restoring tight junction protein expression as well as suppressing expression of inflammatory cytokines.2.At 24 hours after ischemia,the protein levels of Surl and Trpm4 were increased while Surl was upregulated in neurovascular unit,involving neurons,microglia,vascular epithelial cells.3.At 24 hours after ischemia,compared with WT mice,Trpm4-/-mice showed less neurological deficit,smaller cerebral infarction,lighter brain edema and more integrity of blood-brain barrier.As expected,glimepiride did not provide additional neuroprotection compared with vehicle in the tMCAO-treated Trpm4-/-mice.ConclusionGlimepiride shows comparable efficacy with glibenclamide in alleviating brain injury after acute ischemic stroke in mice,possibly via targeting the Surl-Trpm4 channel.