Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice
Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice
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Exendin-4 鼻内给药对小鼠脑缺血具有神经保护作用
DOI：
10.1208/s12248-015-9854-1
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发表时间：
2016
期刊：
影响因子：
4.5
通讯作者：
Ma Xue
中科院分区：
文献类型：
--
作者：
Zhang Huinan;Meng Jingru;Zhou Shimeng;Liu Yunhan;Qu Di;Wang Ling;Li Xubo;Wang Ning;Luo Xiaoxing;Ma Xue
Exendin-4被认为是一种很有前途的治疗脑缺血的药物。为了确定鼻内毒蜥外泌肽-4的神经保护作用，在大脑中动脉闭塞（MCAO）手术之前，C57 BL/6 J小鼠每天鼻内施用毒蜥外泌肽-4，持续7天。与腹腔内给予相同剂量相比，鼻内给予exendin-4会产生更高的脑浓度和更低的血浆浓度。缺血24小时后分析神经功能缺损和梗死灶体积。鼻内给药exendin-4通过减少神经功能缺损评分和梗死体积在经历MCAO的C57 BL/6小鼠中表现出显著的神经保护作用。用shRNA敲除GLP-1 R可阻断exendin-4的神经保护作用。然而，毒蜥外泌肽-4对葡萄糖和胰岛素水平没有影响，这表明神经保护作用是由脑中GLP-1 R的激活介导的。Exendin-4鼻内给药恢复了促凋亡蛋白和抗凋亡蛋白之间的平衡，并降低了Caspase-3的表达。其抗凋亡作用是通过cAMP/PKA和PI 3 K/Akt途径介导的。这些结果提供了证据，证明exendin-4鼻内给药在MCAO小鼠中发挥了由抗凋亡机制介导的神经保护作用，并通过脑中的GLP-1 R通路保护神经元免受缺血性损伤。鼻内给药exendin-4可能是治疗缺血性卒中的一种有前途的策略。
Exendin-4 is now considered as a promising drug for the treatment of cerebral ischemia. To determine the neuroprotective effects of intranasal exendin-4, C57BL/6J mice were intranasally administered with exendin-4 daily for 7 days before middle cerebral artery occlusion (MCAO) surgery. Intranasally administered exendin-4 produced higher brain concentrations and lower plasma concentrations when compared to identical doses administered interperitoneally. Neurological deficits and volume of infarcted lesions were analyzed 24 h after ischemia. Intranasal administration of exendin-4 exhibited significant neuroprotection in C57BL/6 mice subjected to MCAO by reducing neurological deficit scores and infarct volume. The neuroprotective effects of exendin-4 were blocked by the knockdown of GLP-1R with shRNA. However, exendin-4 has no impact on glucose and insulin levels which indicated that the neuroprotective effect was mediated by the activation of GLP-1R in the brain. Exendin-4 intranasal administration restored the balance between pro- and anti-apoptotic proteins and decreased the expression of Caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. These findings provided evidence that exendin-4 intranasal administration exerted a neuroprotective effect mediated by an anti-apoptotic mechanism in MCAO mice and protected neurons against ischemic injury through the GLP-1R pathway in the brain. Intranasal delivery of exendin-4 might be a promising strategy for the treatment of ischemic stroke.