Targeting the Glutamatergic System to Counteract Soman Toxicity in Immature Rats

 描述（由申请方提供）：神经性毒剂是一种强效有机磷毒素，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连接处的积累产生外周胆碱能危象，并且在脑中诱导癫痫发作和癫痫持续状态（SE）。如果没有及时的药物干预，死亡将接踵而至，或者如果死亡被预防但SE未被控制，将导致脑损伤，并产生长期的神经和行为后果。2013年8月，叙利亚发生沙林毒气袭击事件，造成1,400名平民死亡，其中426名是儿童，这一灾难性后果再次将准备就绪的问题以及现有的医疗对策是否能够挽救生命和防止暴露的长期健康后果的问题摆在了最前沿。尽管美国儿科学会指出了儿童更容易受到神经毒剂毒性影响的原因，但由于缺乏未成熟动物的数据，因此关于保护儿科人群的适当对策的信息很少。在这里，我们建议测试LY 293558的组合，AMPA/GluR 5（GluK 1）受体拮抗剂，与caramiphen（CRM），抗毒蕈碱与NMDA受体拮抗剂的属性，对梭曼诱导的癫痫发作，脑损伤，行为缺陷，和病理生理学改变的大脑区域，这些缺陷的基础上，在12日龄和21日龄的大鼠。我们先前已经发现LY 293558和CRM在成年大鼠中是有效的抗惊厥治疗，其中LY 293558具有更快的癫痫发作抑制作用和更大的神经保护作用。最近，我们发现当LY 293558和CRM联合给药时，结果远远上级单独给药时获得的结果;癫痫发作在不到10分钟内终止，神经元变性被完全阻止，第二天大鼠看起来绝对健康，没有体重减轻。考虑到发育中的大脑中的高NMDA受体活性及其在兴奋性毒性中的作用，靶向未成熟大鼠中的NMDA能系统以防止神经毒剂毒性，使用向LY 293558添加NMDA拮抗剂的组合疗法可能是最有效的治疗。

 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.