Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3591-6. doi: 10.1073/pnas.1218498110. Epub 2013 Feb 11.
Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood-brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.
前列腺素 E2 目前被广泛认为在大脑炎症和损伤中发挥关键作用，尽管其负责的前列腺素受体尚未完全确定。我们开发了一种针对前列腺素 E2 受体亚型 EP2 的有效且选择性拮抗剂 TG6-10-1，其药代动力学特征足以在体内使用。我们发现，在匹罗卡品诱导的癫痫持续状态（SE）小鼠模型中，全身性给予 TG6-10-1 完全再现了主要前脑神经元中环氧合酶-2 条件性缺失的效果，即延迟死亡率降低、体重减轻恢复加速、脑炎症减少、血脑屏障开放预防和海马神经保护，而不会急性改变癫痫发作。人类的持续性 SE 会导致高死亡率和发病率，这与大脑炎症和损伤有关，但目前唯一有效的治疗方法是使用抗惊厥药尽快停止癫痫发作，以防止脑损伤。我们的结果表明，前列腺素受体 EP2 与神经炎症和神经退行性变密切相关，并且表明 EP2 受体拮抗作用是治疗 SE 的辅助治疗策略。
