Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilian-University, Koeniginstr. 16, D-80539 Munich, Germany.
Epilepsy Res. 2010 Sep;91(1):57-65. doi: 10.1016/j.eplepsyres.2010.06.012. Epub 2010 Jul 24.
The prostaglandin E2 EP1 receptor as well as the inflammatory enzyme cyclooxygenase-2 have been suggested as targets for disease modulation, improvement of therapeutic response, and restoration of pharmacosensitivity in epilepsies. Translational development of respective add-on approaches requires careful analysis of putative effects on ictogenesis. Therefore we evaluated the impact of the EP1 receptor antagonist SC-51089, the EP1 receptor agonist misoprostol and the COX-2 inhibitors celecoxib and NS-398 in the mouse amygdala kindling model of temporal lobe epilepsy. Neither celecoxib nor NS-398 affected the generation, spread and termination of seizure activity. Whereas SC-51089 did not affect the seizure threshold, the highest dose (30mg/kg) significantly decreased the seizure severity when administered 60min before stimulation. Moreover, SC-51089 significantly prolonged seizure duration at the highest dose. The EP1 receptor agonist misoprostol exerted contrasting effects on seizure duration with a significant decrease in the duration of motor seizure activity. The data suggest that doses of COX-2 inhibitors and EP1 receptor antagonists which exert disease modulating or antiepileptic drug potentiating effects do not negatively affect seizure control in temporal lobe epilepsy. The contrasting impact of the EP1 receptor antagonist and agonist suggests that EP1 receptors can influence endogenous mechanisms involved in termination of seizure activity.
前列腺素 E2 EP1 受体以及炎症酶环氧化酶-2 已被提议作为疾病调节、改善治疗反应和恢复癫痫中药物敏感性的靶点。各自的附加方法的转化开发需要仔细分析对癫痫发生的潜在影响。因此，我们评估了 EP1 受体拮抗剂 SC-51089、EP1 受体激动剂米索前列醇和 COX-2 抑制剂塞来昔布和 NS-398 在颞叶癫痫的小鼠杏仁核点燃模型中的影响。塞来昔布和 NS-398 均不影响癫痫发作活动的产生、传播和终止。虽然 SC-51089 不影响癫痫发作阈值，但在刺激前 60 分钟给予最高剂量（30mg/kg）时，显著降低癫痫发作的严重程度。此外，SC-51089 在最高剂量时显著延长癫痫持续时间。EP1 受体激动剂米索前列醇对癫痫持续时间产生相反的影响，运动性癫痫发作活动的持续时间显著缩短。数据表明，发挥疾病调节或增强抗癫痫药物作用的 COX-2 抑制剂和 EP1 受体拮抗剂的剂量不会对颞叶癫痫的癫痫发作控制产生负面影响。EP1 受体拮抗剂和激动剂的对比影响表明，EP1 受体可以影响参与癫痫发作活动终止的内源性机制。
