Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, 60515, USA.
Pharmazz Inc. Research and Development, Willlowbrook, IL, USA.
Sci Rep. 2020 Jul 29;10(1):12737. doi: 10.1038/s41598-020-69673-w.
The development of effective drugs for stroke is urgently required as it is the 2nd largest killer in the world and its incidence is likely to increase in the future. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat acute cerebral ischemic stroke. However, the mechanism of ETBR mediated neural regeneration and repair remains elusive. In this study, a permanent middle cerebral artery occluded (MCAO) rat model was used. Sovateltide (an ETBR agonist) injected intravenously showed better survival and neurological and motor function improvement than control. Higher neuronal progenitor cells (NPCs) differentiation along with better mitochondrial morphology and biogenesis in the brain of sovateltide rats were noted. Exposure of cultured NPCs to hypoxia and sovateltide also showed higher NPC differentiation and maturation. This study shows a novel role of ETBR in NPCs and mitochondrial fate determination in cerebral ischemia, and in improving neurological deficit after stroke.
由于中风是世界上第二大致死原因，而且其发病率未来可能会增加，因此迫切需要开发有效的治疗药物。我们已经证明脑内皮素 B 受体（ETBR）是治疗急性脑缺血性中风的潜在靶点。然而，ETBR 介导的神经再生和修复的机制仍不清楚。在这项研究中，使用了永久性大脑中动脉闭塞（MCAO）大鼠模型。静脉注射 Sovateltide（一种 ETBR 激动剂）显示出比对照组更好的生存和神经及运动功能改善。Sovateltide 大鼠的大脑中观察到更高的神经元祖细胞（NPC）分化以及更好的线粒体形态和生物发生。将培养的 NPC 暴露于缺氧和 Sovateltide 中也显示出更高的 NPC 分化和成熟。这项研究表明 ETBR 在 NPC 中和脑缺血中线粒体命运决定以及中风后改善神经功能缺损方面具有新的作用。
