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

基本信息

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
项目类别：
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

项目摘要

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）：神经毒剂是强效的有机磷毒素，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，就会导致死亡，或者如果死亡得到预防但 SE 没有得到控制，脑损伤就会发生。 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，造成了长期的神经和行为后果，这再次使准备情况以及是否做好准备的问题成为人们关注的焦点。现有的医疗对策可以挽救生命并防止接触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，但有关适当的信息却很少。由于缺乏未成熟动物的数据，因此我们建议测试 LY293558（一种 AMPA/GluR5(GluK1) 受体拮抗剂）与 caramiphen (CRM)（一种具有 NMDA 受体拮抗特性的抗毒蕈碱剂）的组合。对抗索曼引起的癫痫发作、脑损伤、行为缺陷以及这些缺陷背后的大脑区域的病理生理学改变， 12 日龄和 21 日龄大鼠我们之前发现 LY293558 和 CRM 对成年大鼠是有效的抗惊厥治疗，其中 LY293558 具有更快的癫痫抑制作用和更强的神经保护作用。 LY293558和CRM联合给药，效果远优于每种药物单独给药所获得的结果，癫痫发作在不到20分钟内终止； 10 分钟后，神经元变性被完全阻止，并且第二天大鼠看起来绝对健康，并且通过使用添加 NMDA 拮抗剂的联合疗法，针对未成熟大鼠的谷氨酸能系统以防止神经毒剂毒性。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，LY293558 可能是最有效的治疗方法。