Department of Pharmaceutical Sciences and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Pharmaceutical Sciences and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Pharmacol Ther. 2020 May;209:107504. doi: 10.1016/j.pharmthera.2020.107504. Epub 2020 Feb 21.
Status epilepticus (SE) is an emergency condition that can cause permanent brain damage or even death when generalized convulsive seizures last longer than 30 min. Controlling the escalation and propagation of seizures quickly and properly is crucial to the prevention of irreversible neuronal death and the associated morbidity. However, SE often becomes refractory to current anticonvulsant medications, which primarily act on ion channels and commonly impose undesired effects. Identifying new molecular targets for SE might lead to adjunctive treatments that can be delivered even when SE is well established. Recent preclinical studies suggest that prostaglandin E2 (PGE) is an essential inflammatory mediator for the brain injury and morbidity following prolonged seizures via activating four G protein-coupled receptors, namely, EP1-EP4. Given that EP2 receptor activation has been identified as a common culprit in several inflammation-associated neurological conditions, such as strokes and neurodegenerative diseases, selective small-molecule antagonists targeting EP2 have been recently developed and utilized to suppress PGE-mediated neuroinflammation. Transient inhibition of the EP2 receptor by these bioavailable and brain-permeable antagonists consistently showed marked anti-inflammatory and neuroprotective effects in several rodent models of SE yet had no noticeable effect on seizures per se. This review provides overviews and perspectives of the EP2 receptor as an emerging target for adjunctive treatment, together with the current first-line anti-seizure drugs, to prevent acute brain inflammation and damage following SE.
癫痫持续状态（SE）是一种紧急情况，如果全身性惊厥持续超过 30 分钟，可能导致永久性脑损伤甚至死亡。快速、正确地控制发作的升级和传播对于预防不可逆的神经元死亡和相关发病率至关重要。然而，SE 通常对目前的抗惊厥药物产生抗药性，这些药物主要作用于离子通道，通常会产生不良影响。确定 SE 的新分子靶点可能会导致辅助治疗，即使 SE 已经确立，也可以进行这种治疗。最近的临床前研究表明，前列腺素 E2（PGE）通过激活四个 G 蛋白偶联受体（即 EP1-EP4），是长时间发作后脑损伤和发病率的重要炎症介质。鉴于 EP2 受体的激活已被确定为几种与炎症相关的神经疾病（如中风和神经退行性疾病）的常见罪魁祸首，因此最近已经开发并利用针对 EP2 的选择性小分子拮抗剂来抑制 PGE 介导的神经炎症。这些可生物利用的和可穿透大脑的拮抗剂对 EP2 受体的短暂抑制在 SE 的几种啮齿动物模型中均显示出明显的抗炎和神经保护作用，但对发作本身没有明显影响。这篇综述提供了 EP2 受体作为辅助治疗的新兴靶点的概述和观点，以及当前的一线抗惊厥药物，以预防 SE 后急性脑炎症和损伤。
