Glimepiride and glibenclamide have comparable efficacy in treating acute ischemic stroke in mice
Glimepiride and glibenclamide have comparable efficacy in treating acute ischemic stroke in mice
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格列美脲和格列本脲治疗小鼠急性缺血性中风具有相当的功效
DOI：
10.1016/j.neuropharm.2019.107845
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发表时间：
2020-01-01
影响因子：
4.7
通讯作者：
Pan, Suyue
中科院分区：
文献类型：
--
作者：
Wang, Xiaoqiang;Chang, Yuan;Pan, Suyue
在临床前及临床研究中，格列本脲均显示出对缺血性损伤的保护作用，推测其机制是通过阻断缺血诱导的重新组装的磺酰脲受体1 - 瞬时受体电位M4（SUR1 - TRPM4）通道。然而，格列本脲可能会引发意想不到的严重低血糖。在此，我们探究了另一种安全性更佳的磺酰脲类药物格列美脲，是否与格列本脲具有相当的疗效，以及TRPM4基因敲除（Trpm4-/- ）是否能发挥类似作用。对遭受短暂大脑中动脉闭塞（tMCAO）的野生型（WT）小鼠，在缺血后随机给予格列本脲（初始剂量10 μg/kg，之后每8小时追加1.2 μg）、三种不同剂量的格列美脲（10 μg/kg、100 μg/kg和1 μg/kg）或赋形剂；而对接受tMCAO处理的Trpm4-/- 小鼠，则随机给予赋形剂或格列美脲。在缺血24小时后，评估神经功能、梗死体积、水肿形成情况、血脑屏障完整性及炎症反应。在接受tMCAO处理的WT小鼠中，10 μg/kg和100 μg/kg的格列美脲在改善Longa评分和抓力测试评分、减少梗死体积、减轻脑水肿、减少伊文思蓝染料和免疫球蛋白G（IgG）外渗、恢复紧密连接蛋白表达以及抑制炎症细胞因子方面，与格列本脲具有相当的疗效。与WT小鼠相比，Trpm4-/- 小鼠表现出更少的神经功能缺损、更小的脑梗死面积、更轻的脑水肿以及更完整的血脑屏障。正如预期，在接受tMCAO处理的Trpm4-/- 小鼠中，与赋形剂相比，格列美脲并未提供额外的神经保护作用。格列美脲在减轻小鼠缺血性脑卒中后脑损伤方面与格列本脲疗效相当，可能是通过作用于SUR1 - TRPM4通道实现的。
Glibenclamide protects against ischemic injury in both preclinical and clinical studies, presumably by blocking the de novo assembled sulfonylurea receptor 1-transient receptor potential M4 (Surl-Trpm4) channel induced by ischemia. However, glibenclamide may cause unexpected serious hypoglycemia. Here, we tested whether glimepiride, another sulfonylurea with better safety, has comparable efficacy with glibenclamide and whether gene deletion of Trpm4 (Trpm4(-/-)) exerts similar effect. Wild-type (WT) mice subjected to temporary middle cerebral artery occlusion (tMCAO) were randomized to receive glibenclamide (an initial dose of 10 mu g/kg and additional doses of 1.2 mu g every 8 h), three different doses of glimepiride (10 mu g/kg, 100 mu g/kg and 1 mu g/kg) or vehicle after ischemia, while tMCAO-treated Trpm4(-/-) mice were randomized to receive vehicle or glimepiride. Neurological function, infarct volume, edema formation, the integrity of blood-brain barrier and inflammatory reaction were evaluated at 24 h after ischemia. In tMCAO-treated WT mice, 10 mu g/kg and 100 mu g/kg glimepiride had comparable efficacy with glibenclamide in improving longa score and 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 inflammatory cytokines. 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. Glimepiride shows comparable efficacy with glibenclamide in alleviating brain injury after ischemic stroke in mice, possibly via targeting the Surl-Trpm4 channel.