Targeting the Glutamatergic System to Counteract Soman Toxicity in Immature Rats

 描述(由申请人提供)：神经毒剂是一种有效的有机磷毒素，主要通过抑制乙酰胆碱酯酶的活性发挥作用。由此产生的乙酰胆碱在突触交界处的积聚会导致外周胆碱能危象，并在大脑中诱发癫痫发作和癫痫持续状态(SE)。如果没有及时的药物干预，死亡就会随之而来，或者如果死亡得到预防，但SE得不到控制，就会导致脑损伤，并造成长期的神经和行为后果。2013年8月，叙利亚发生沙林袭击，造成1400名平民死亡，其中426人是儿童，造成的破坏性后果再次将准备就绪以及现有的医疗对策是否能够挽救生命和防止暴露在危险中的长期健康后果摆在首位。尽管美国儿科学会指出了儿童更容易受到神经毒剂中毒的原因，但由于缺乏未成熟动物的数据，有关保护儿童种群的适当对策的信息非常少。在这里，我们建议测试AMPA/GluR5(GluK1)受体拮抗剂LY293558与具有NMDA受体拮抗特性的抗肌松药卡拉米芬(CRM)的组合，以对抗梭曼诱导的癫痫发作、脑损伤、行为缺陷以及导致这些缺陷的大脑区域的病理生理变化，在12天和21天出生的大鼠。我们先前已经发现LY293558和CRM是成年大鼠有效的抗惊厥药物，其中LY293558具有更快的惊厥抑制作用和更强的神经保护作用。最近，我们发现，LY293558和CRM联合给药，效果远远优于单独给药，不到10分钟就能终止癫痫发作，完全防止神经元变性，第二天大鼠看起来完全健康，体重没有下降。考虑到发育中大脑中NMDA受体的高活性及其在兴奋性毒性中的作用，以未成熟大鼠的谷氨酸能系统为靶点以预防神经毒剂毒性的联合疗法，在LY293558中添加NMDA拮抗剂，可能是一种最有效的治疗方法。

 DESCRIPTION (provided by applicant): Nerve agents are potent, organophosphorus toxins that act primarily by inhibiting the activity of acetylcholinesterase. The resulting accumulation o acetylcholine at synaptic junctions produces peripheral cholinergic crisis, and, in the brain, induces seizures and status epilepticus (SE). Without timely pharmacological intervention, death will ensue, or if death is prevented but the SE is not controlled, brain damage will result, with long-term neurological and behavioral consequences. The devastating effects of the sarin attack in Syria, in August of 2013, where 1,400 civilians were killed, 426 of which were children, brought again to the forefront the question of readiness and whether the existing medical countermeasures can save lives and protect against the long-term health consequences of exposure. Although the American Academy of Pediatrics have pointed out the reasons that children are more vulnerable to nerve agent toxicity, there is very little information on the appropriate countermeasures to protect the pediatric population, as data in immature animals are lacking. Here, we propose to test the combination of LY293558, an AMPA/GluR5(GluK1) receptor antagonist, with caramiphen (CRM), an antimuscarinic with NMDA receptor antagonistic properties, against soman-induced seizures, brain damage, behavioral deficits, and pathophysiological alterations in brain regions that underlie these deficits, in 12-day-old and 21-day-old rats. We have previously found that LY293558 and CRM are efficacious anticonvulsant treatments in adult rats, with the LY293558 having a faster seizure- suppressing action and greater neuroprotective effects. Recently, we discovered that when LY293558 and CRM are administered in combination, the results are far superior to those obtained when each drug is given alone; seizures are terminated in less than 10 min, neuronal degeneration is completely prevented, and the rats appear absolutely healthy the next day and have no weight loss. Targeting the glutamatergic system in immature rats to prevent nerve agent toxicity, with the use of a combination therapy that adds an NMDA antagonist to LY293558, is likely to be a most efficacious treatment, considering the high NMDA receptor activity in the developing brain, and its role in excitotoxicity.