Prostaglandin-E₂ (PGE₂), an important mediator of inflammation, achieves its functions via four different G protein–coupled receptors (EP1, EP2, EP3, and EP4). We previously demonstrated that the EP2 receptor plays a proinflammatory and neurodegenerative role after status epilepticus (SE). We recently developed TG8-260 as a second-generation highly potent and selective EP2 antagonist. Here, we investigate whether TG8-260 is anti-inflammatory and combats neuropathology caused by pilocarpine-induced SE in rats. Adult male Sprague–Dawley rats were injected subcutaneously with pilocarpine (380–400 mg/kg) to induce SE. Following 60 min of SE, the rats were administered three doses of TG8-260 or vehicle and were allowed to recover. Neurodegeneration, neuroinflammation, gliosis, and blood–brain barrier (BBB) integrity were examined 4 days after SE. The results confirmed that pilocarpine-induced SE results in hippocampal neurodegeneration and a robust inflammatory response that persists days after SE. Furthermore, inhibition of the EP2 receptor by TG8-260 administered beginning 2 h after SE significantly reduced hippocampal neuroinflammation and gliosis but, in distinction to the earlier generation EP2 antagonist, did not mitigate neuronal injury or BBB breakdown. Thus, attenuation of neuroinflammation and gliosis is a common feature of EP2 inhibition following SE.

前列腺素-E ₂ (PGE ₂)，一种重要的炎症介质，通过四种不同的 G 蛋白偶联受体（EP1、EP2、EP3 和 EP4）实现其功能。我们以前证明 EP2 受体在癫痫持续状态 (SE) 后发挥促炎和神经退行性作用。我们最近开发了 TG8-260 作为第二代高效选择性 EP2 拮抗剂。在这里，我们研究了 TG8-260 是否具有抗炎作用并对抗由毛果芸香碱诱导的大鼠 SE 引起的神经病理学。成年雄性 Sprague-Dawley 大鼠皮下注射毛果芸香碱 (380-400 mg/kg) 以诱导 SE。在 SE 60 分钟后，给大鼠施用三剂 TG8-260 或载体并使其恢复。SE 后 4 天检查神经退行性变、神经炎症、神经胶质增生和血脑屏障 (BBB) 完整性。结果证实，毛果芸香碱诱导的 SE 导致海马神经变性和 SE 后持续数天的强烈炎症反应。此外，在 SE 后 2 小时开始施用 TG8-260 对 EP2 受体的抑制显着减少了海马神经炎症和神经胶质增生，但与早期的 EP2 拮抗剂不同，并未减轻神经元损伤或 BBB 分解。因此，神经炎症和神经胶质增生的减弱是 SE 后 EP2 抑制的共同特征。与上一代 EP2 拮抗剂不同，没有减轻神经元损伤或 BBB 分解。因此，神经炎症和神经胶质增生的减弱是 SE 后 EP2 抑制的共同特征。与上一代 EP2 拮抗剂不同，没有减轻神经元损伤或 BBB 分解。因此，神经炎症和神经胶质增生的减弱是 SE 后 EP2 抑制的共同特征。