Department of Biomedical Informatics, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, 38 Xueyuan Rd., Beijing 100191, China.
Int J Mol Sci. 2023 Jul 31;24(15):12244. doi: 10.3390/ijms241512244.
Stroke is a major cause of fatalities and disabilities around the world, yet the available treatments for it are still limited. The quest for more efficacious drugs and therapies is still an arduous task. LY2922470 is currently used as a G protein-coupled receptor 40 (GPR40) agonist for the treatment of type 2 diabetes. Previous studies have reported protective effects of other GPR40 activators on the brain; however, it remains unclear whether LY2922470 could be a new stroke therapy and improve the stroke-induced brain damage. Here, we first reveal that the transcriptomic gene signature induced by LY2922470 is highly similar to those induced by some agents being involved in defending from cerebrovascular accidents and transient ischemic attacks, including acetylsalicylic acid, progesterone, estradiol, dipyridamole, and dihydroergotamine. This result thus suggests that LY2922470 could have protective effects against ischemic stroke. As a result, further experiments show that giving the small molecule LY2922470 via oral administration or intraperitoneal injection was seen to have a positive effect on neuroprotection with a reduction in infarct size and an improvement in motor skills in mice. Finally, it was demonstrated that LY2922470 could successfully mitigate the harm to the brain caused by ischemic stroke.
中风是全球范围内导致死亡和残疾的主要原因，但可用的治疗方法仍然有限。寻找更有效的药物和治疗方法仍然是一项艰巨的任务。LY2922470 目前被用作治疗 2 型糖尿病的 G 蛋白偶联受体 40（GPR40）激动剂。先前的研究报告了其他 GPR40 激活剂对大脑的保护作用；然而，目前尚不清楚 LY2922470 是否可以成为一种新的中风治疗方法，并改善中风引起的脑损伤。在这里，我们首先揭示 LY2922470 诱导的转录组基因特征与那些涉及防御脑血管意外和短暂性脑缺血发作的药物诱导的基因特征高度相似，包括乙酰水杨酸、孕酮、雌二醇、双嘧达莫和二氢麦角胺。这一结果表明，LY2922470 可能对缺血性中风具有保护作用。因此，进一步的实验表明，通过口服或腹腔注射给予小分子 LY2922470 对神经保护具有积极作用，可减少梗死面积并改善小鼠的运动技能。最后，证明 LY2922470 可以成功减轻缺血性中风对大脑造成的伤害。
