Targeting the Glutamatergic System to Counteract Soman Toxicity in Immature Rats

针对未成熟大鼠的谷氨酸能系统抵消梭曼毒性

• 批准号: 9002644
• 负责人: Maria F. Braga
• 金额: $ 37.19万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002644
• 关键词: 4 year old; Academy; Accounting; Acetylcholine; Acetylcholinesterase; Adult; Affect; Age; American; Animal Model; Anticonvulsants; Behavior; Behavioral; Blood - brain barrier anatomy; Body Surface Area; Body Weight decreased; Brain; Brain Injuries; Brain region; Breathing; Cessation of life; Child; Childhood; Combined Modality Therapy; Communities; Data; Development; Drug Kinetics; Event; Exposure to; Female; Gender; Glutamates; Government; Health; Human; Intervention; Lead; Lethal Dose 50; Life; Medical; Modification; Muscarinic Antagonists; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Nature; Nerve Degeneration; Neurologic; Newborn Infant; Pediatrics; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacological Treatment; Play; Population; Predisposition; Property; Rattus; Readiness; Research; Respiration; Role; Sarin; Seizures; Skin; Soman; Staging; Status Epilepticus; Synapses; Syria; System; Testing; Toxic effect; Toxin; age related; base; behavior test; cholinergic; density; drug testing; efficacy testing; excitotoxicity; immature animal; improved; killings; male; mass casualty; mature animal; nerve agent; neuronal circuitry; neuropathology; novel; novel therapeutic intervention; postnatal; prevent; public health relevance; receptor; response; vapor

 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.

 描述（由申请人提供）：神经毒剂是有效的有机磷毒素，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连接处的积累会产生外周胆碱能危象，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 没有得到控制，就会导致脑损伤，从而产生长期的神经和行为后果。 2013 年 8 月，叙利亚沙林毒气袭击造成 1,400 名平民死亡，其中 426 名儿童，其造成的破坏性影响再次使人们关注准备就绪的问题，以及现有的医疗对策是否能够挽救生命并防止暴露造成的长期健康后果。尽管美国儿科学会指出了儿童更容易受到神经毒剂毒性的原因，但由于缺乏未成熟动物的数据，因此有关保护儿科人群的适当对策的信息很少。在此，我们建议在 12 日龄和 21天大的老鼠。我们之前发现LY293558和CRM是成年大鼠有效的抗惊厥治疗，其中LY293558具有更快的癫痫抑制作用和更强的神经保护作用。最近，我们发现LY293558和CRM联合给药时，效果远远优于每种药物单独给药时的效果；癫痫发作在不到 10 分钟内终止，神经元变性被完全预防，并且大鼠第二天看起来绝对健康并且体重没有减轻。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，通过使用在 LY293558 中添加 NMDA 拮抗剂的联合疗法，针对未成熟大鼠的谷氨酸能系统来预防神经毒剂毒性，可能是最有效的治疗方法。