Novel GLP-1R/GIPR co-agonist "twincretin" is neuroprotective in cell and rodent models of mild traumatic brain injury.
Novel GLP-1R/GIPR co-agonist "twincretin" is neuroprotective in cell and rodent models of mild traumatic brain injury.
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DOI：
10.1016/j.expneurol.2016.11.005
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发表时间：
2017-03
影响因子：
5.3
通讯作者：
Greig NH
中科院分区：
文献类型：
--
作者：
Tamargo IA;Bader M;Li Y;Yu SJ;Wang Y;Talbot K;DiMarchi RD;Pick CG;Greig NH
几种获批用于治疗2型糖尿病（T2DM）的肠降血糖素受体激动剂在神经退行性疾病的细胞和动物模型中显示出神经保护作用。最近，一种合成的双重肠促胰岛素受体激动剂（昵称为“twincretin”）在T2DM小鼠和猴模型中显示出改善单受体激动剂的代谢获益。在当前的研究中，在轻度创伤性脑损伤（mTBI）的细胞和小鼠模型中探索twincretin的神经保护作用，mTBI是幼儿、青少年和老年人神经变性的普遍原因。Twincretin在本文中显示对两种不同受体具有活性，剂量依赖性地增加神经营养CREB途径中中间体的水平，并增强暴露于毒性浓度的谷氨酸盐和过氧化氢的人神经母细胞瘤细胞的活力，模拟mTBI后脑中的炎症状况的损伤。此外，twincretin显示出在这些相同细胞中改善单一肠促胰岛素受体激动剂的神经营养作用。最后，当在mTBI后施用时，显示临床上可转化剂量的twincretin完全恢复由mTBI诱导的视觉和空间记忆缺陷，如在体重下降近距离头部损伤的小鼠模型中所评估的。这些结果确立了twincretin作为一种新的神经保护剂，并表明它可以通过双重激动作用改善单一肠促胰岛素受体激动剂的作用。
Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed “twincretin,” was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.
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