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Inhibiting the PGE2 Receptor EP2 Mitigates Excitotoxicity and Ischemic Injury.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-06-25 , DOI: 10.1021/acsptsci.0c00040
Lexiao Li 1 , Ying Yu 1 , Ruida Hou 1 , Jiukuan Hao 2 , Jianxiong Jiang 1
Affiliation  

Prostaglandin E2 (PGE2) is elevated in the brain by excitotoxic insults and, in turn, aggravates the neurotoxicity mainly through acting on its Gαs-coupled receptor EP2, inspiring a therapeutic strategy of targeting this key proinflammatory pathway. Herein, we investigated the effects of several highly potent and selective small-molecule antagonists of the EP2 receptor on neuronal excitotoxicity both in vitro and in vivo. EP2 inhibition by these novel compounds largely decreased the neuronal injury in rat primary hippocampal cultures containing both neurons and glia that were treated with N-methyl-d-aspartate and glycine. Using a bioavailable and brain-permeant analogue TG6-10-1 that we recently developed to target the central EP2 receptor, we found that the poststroke EP2 inhibition in mice decreased the neurological deficits and infarct volumes as well as downregulated the prototypic inflammatory cytokines in the brain after a transient ischemia. Our preclinical findings together reinforced the notion that targeting the EP2 receptor represents an emerging therapeutic strategy to prevent the neuronal injury and inflammation following ischemic stroke.

中文翻译:


抑制 PGE2 受体 EP2 可减轻兴奋性毒性和缺血性损伤。



前列腺素 E2 (PGE 2 ) 在大脑中因兴奋性毒性损伤而升高,反过来,主要通过作用于其 Gα s偶联受体 EP2 来加剧神经毒性,从而激发了针对这一关键促炎途径的治疗策略。在此,我们研究了几种高效、选择性的 EP2 受体小分子拮抗剂对体外和体内神经元兴奋毒性的影响。这些新化合物对 EP2 的抑制很大程度上减少了用N-甲基-d-天冬氨酸和甘氨酸处理的含有神经元和神经胶质细胞的大鼠原代海马培养物中的神经元损伤。使用我们最近开发的针对中枢 EP2 受体的生物利用度和脑渗透性类似物 TG6-10-1,我们发现中风后 EP2 抑制可减少小鼠的神经功能缺损和梗塞体积,并下调小鼠体内的原型炎症细胞因子。短暂性脑缺血后的大脑。我们的临床前研究结果共同强化了这样一种观念,即针对 EP2 受体代表了一种新兴的治疗策略,可预防缺血性中风后的神经元损伤和炎症。
更新日期:2020-08-14
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