An Orally Active Allosteric GLP-1 Receptor Agonist Is Neuroprotective in Cellular and Rodent Models of Stroke.
An Orally Active Allosteric GLP-1 Receptor Agonist Is Neuroprotective in Cellular and Rodent Models of Stroke.
复制标题
口服活性变构 GLP-1 受体激动剂在细胞和啮齿动物中风模型中具有神经保护作用
DOI：
10.1371/journal.pone.0148827
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Zhang H;Liu Y;Guan S;Qu D;Wang L;Wang X;Li X;Zhou S;Zhou Y;Wang N;Meng J;Ma X
糖尿病是中风发病的主要危险因素。胰升糖素样肽-1受体(GLP-1R)激动剂已被临床用于治疗糖尿病，并被报道对缺血性中风具有神经保护作用。喹恶啉(DMB)是GLP-1R的激动剂和变构调节剂，具有增强GLP-1与其受体亲和力的作用。本研究旨在评价DMB对短暂性局灶性脑缺血的神经保护作用。在培养的皮质神经元中，DMB激活GLP-1R，导致细胞内cAMP水平升高，EC50值约为exendin-4的100倍。缺氧缺糖(OGD)诱导神经元死亡，DMB可保护神经元免受坏死和凋亡的影响。DMB的神经保护作用可被GLP-1R shRNA阻断，但不能被GLP-1R拮抗剂阻断。C57BL/6小鼠在大脑中动脉闭塞(MCAO)前30min灌胃给予DMB。DMB能明显缩小脑缺血再灌流所致的脑梗塞面积和神经功能缺失。其神经保护作用是通过cAMP-PKA-CREB信号通路激活GLP-1R实现的。DMB通过调节Bcl2家族成员发挥抗细胞凋亡作用。这些结果为小分子GLP-1R激动剂DMB减轻短暂性局灶性脑缺血损伤和抑制MCAO诱导的神经细胞凋亡提供了证据。综上所述，这些数据表明DMB是一种潜在的抗脑缺血的神经保护剂。
Diabetes is a major risk factor for the development of stroke. Glucagon-like peptide-1 receptor (GLP-1R) agonists have been in clinical use for the treatment of diabetes and also been reported to be neuroprotective in ischemic stroke. The quinoxaline 6,7-dichloro-2-methylsulfonyl-3-N-tert- butylaminoquinoxaline (DMB) is an agonist and allosteric modulator of the GLP-1R with the potential to increase the affinity of GLP-1 for its receptor. The aim of this study was to evaluate the neuroprotective effects of DMB on transient focal cerebral ischemia. In cultured cortical neurons, DMB activated the GLP-1R, leading to increased intracellular cAMP levels with an EC50 value about 100 fold that of exendin-4. Pretreatment of neurons with DMB protected against necrotic and apoptotic cell death was induced by oxygen-glucose deprivation (OGD). The neuroprotective effects of DMB were blocked by GLP-1R knockdown with shRNA but not by GLP-1R antagonism. In C57BL/6 mice, DMB was orally administered 30 min prior to middle cerebral artery occlusion (MCAO) surgery. DMB markedly reduced the cerebral infarct size and neurological deficits caused by MCAO and reperfusion. The neuroprotective effects were mediated by activation of the GLP-1R through the cAMP-PKA-CREB signaling pathway. DMB exhibited anti-apoptotic effects by modulating Bcl-2 family members. These results provide evidence that DMB, a small molecular GLP-1R agonist, attenuates transient focal cerebral ischemia injury and inhibits neuronal apoptosis induced by MCAO. Taken together, these data suggest that DMB is a potential neuroprotective agent against cerebral ischemia.