One of the devastating effects of acute exposure to organophosphates, like nerve agents, is the induction of severe and prolonged status epilepticus (SE), which can cause death, or brain damage if death is prevented. Seizures after exposure are initiated by muscarinic receptor hyperstimulation—after inhibition of acetylcholinesterase by the organophosphorus agent and subsequent elevation of acetylcholine—but they are reinforced and sustained by glutamatergic hyperexcitation, which is the primary cause of brain damage. Diazepam is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam is currently under consideration. However, clinical data derived from the treatment of SE of any etiology, as well as studies on the control of nerve agent-induced SE in animal models, have indicated that diazepam and midazolam control seizures only temporarily, their antiseizure efficacy is reduced as the latency of treatment from the onset of SE increases, and their neuroprotective efficacy is limited or absent. Here, we review data on the discovery of a novel anticonvulsant and neuroprotectant, LY293558, an AMPA/GluK1 receptor antagonist. Treatment of soman-exposed immature, young-adult, and aged rats with LY293558, terminates SE with limited recurrence of seizures, significantly protects from brain damage, and prevents long-term behavioral deficits, even when LY293558 is administered 1 h post-exposure. More beneficial effects and complete neuroprotection is obtained when LY293558 administration is combined with caramiphen, which antagonizes NMDA receptors. Further efficacy studies may bring the LY293558 + caramiphen combination therapy on the pathway to approval for human use.

急性暴露于有机磷酸盐（如神经毒剂）的毁灭性影响之一是诱发严重和长时间的癫痫持续状态（SE），如果导致死亡，可能会导致死亡或脑部损伤。暴露后的癫痫发作是由毒蕈碱受体过度刺激引起的（有机磷试剂抑制乙酰胆碱酯酶并随后引起乙酰胆碱升高），但谷氨酸能过度兴奋会加剧和维持癫痫发作，这是脑损伤的主要原因。地西p是FDA批准的用于治疗神经药诱发的SE的抗惊厥药，目前正在考虑用咪达唑仑替代。但是，从任何病因治疗SE得出的临床数据，以及在动物模型中控制神经毒剂诱导的SE的研究，已经表明地西epa和咪达唑仑仅暂时控制癫痫发作，随着从SE发作开始的治疗潜伏期增加，它们的抗癫痫发作功效降低，并且它们的神经保护功效有限或不存在。在这里，我们审查关于新型抗惊厥药和神经保护剂LY293558（一种AMPA / GluK1受体拮抗剂）的发现的数据。LY293558治疗暴露于人的未成熟，成年和老年大鼠，即使发作后1 h服用LY293558，也可以终止SE并限制癫痫发作的复发，显着保护其免受脑损伤，并防止长期的行为缺陷。当LY293558的给药与拮抗NMDA受体的caramiphen组合使用时，可获得更多的有益效果和完全的神经保护作用。