Antiglutamatergic Therapy to Protect the Immature Brain Against Nerve Agents

抗谷氨酸治疗可保护未成熟的大脑免受神经毒剂的侵害

• 批准号: 9769166
• 负责人: Maria F. Braga
• 金额: $ 44.96万
• 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: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769166
• 关键词: AMPA Receptors; Academy; Acetylcholine; Acetylcholinesterase; Acute; Adult; Affect; Age; Aggressive behavior; American; Amygdaloid structure; Animals; Anticonvulsants; Area; Atrophic; Behavior; Behavioral; Benzodiazepines; Body Surface Area; Body Weight Changes; Body Weight decreased; Brain; Brain Injuries; Brain region; Breathing; Cessation of life; Chemical Weapons; Child; Childhood; Clinical; Cognitive; Cognitive deficits; Combined Modality Therapy; Data; Development; Diazepam; Drug Kinetics; Electroencephalography; Emotional; Event; Exposure to; FDA approved; Female; Functional disorder; Glutamates; Hippocampus (Brain); Infant; Injury; International; Interneurons; Investigation; Kainic Acid Receptors; Knowledge; Lead; Measures; Mediating; Midazolam; Modeling; Morbidity - disease rate; Muscarinic Antagonists; Muscarinics; N-Methyl-D-Aspartate Receptors; Names; Nature; Nerve Degeneration; Neurologic; Neurologic Deficit; Neurons; Pediatrics; Peripheral; Permeability; Pharmaceutical Preparations; Phase; Physiological; Pilocarpine; Plasma; Population; Predisposition; Property; Rattus; Recovery; Recurrence; Research; Respiration; Role; Savings; Seizures; Skin; Soman; Status Epilepticus; Survival Rate; Synapses; Terrorism; Testing; Time; Toxic effect; Toxin; War; animal data; behavior measurement; cholinergic; cognitive development; comparative efficacy; density; excitotoxicity; immature animal; indexing; male; mass casualty; nerve agent; neuron loss; neuropathology; neuroprotection; postnatal; preclinical development; prevent; receptor; response; vapor; young adult

Nerve agents are lethal chemical weapons that have been used in war and in terrorist attacks, with devastating consequences; the possibility that they will be used again against civilians is presently very high. One of the clinical manifestations of exposure to nerve agents is seizure activity progressing to status epilepticus (SE) which can lead to death, or brain damage with long-term neurological and behavioral consequences. The American Academy of Pediatrics have pointed out the reasons that children may be more vulnerable to nerve agent toxicity; yet, there is very little information on the appropriate countermeasures to protect the pediatric population, as data in immature animals are lacking. The FDA has approved diazepam as the anticonvulsant treatment for nerve agent-induced SE, irrespective of the age of the victim. However, there is sufficient evidence indicating that diazepam does not have good neuroprotective efficacy, and, in the developing brain, it may worsen the injury induced by the SE. Animal data are, therefore, needed to provide knowledge on how to protect the immature brain from damage in the event of nerve agent exposure, taking into account that GABAA receptor-mediated activity can be excitatory in the developing brain, while glutamatergic activity and particularly the activity of NMDA receptors, which are well known for their role in excitotoxicity, is very pronounced. We have already demonstrated the efficacy of LY293558, an AMPA/GluK1 receptor antagonist, in stopping seizures and significantly reducing neuropathology and long-term deficits in adult rats exposed to soman. We have also tested the combination of LY293558 with caramiphen, an antimuscarinic with NMDA receptor antagonistic properties, and found that it terminates soman-induced seizures faster than LY293558 alone, provides full protection from neuronal damage in all brain regions examined, and the recovery of the animals is swift with no weight loss. In the present application, we propose to test and compare the efficacy of LY293558+caramiphen with that of LY293558 alone, and with two benzodiazepines, diazepam and midazolam, against soman, in male and female rats of postnatal age 7, 12, and 21 days; anticonvulsant treatments will be administered 1 h after soman exposure. We hypothesize that LY293558+caramiphen will provide more benefits than LY293558 alone, and will prove to be far superior to both diazepam and midazolam in stopping soman-induced seizures, preventing neuronal degeneration, neuronal loss, GABAergic interneuronal loss, atrophy and pathophysiological alterations in the amygdala and hippocampus, as well as cognitive, behavioral, and neurological deficits studied up to 6 months postexposure. The data acquired will contribute immensely in developing safe and efficacious countermeasures for protecting the lives of infants and children and prevent long-term morbidities.

神经毒剂是一种致命的化学武器，曾被用于战争和恐怖袭击， 目前，这些武器再次被用来对付平民的可能性很高。之一 暴露于神经毒剂的临床表现是癫痫发作活动进展为癫痫持续状态（SE） 这可能导致死亡或脑损伤，并造成长期的神经和行为后果。的 美国儿科学会指出，儿童可能更容易受到神经 药物毒性;然而，关于保护儿科患者的适当对策的信息很少。 由于缺乏未成熟动物的数据，FDA已经批准安定作为抗惊厥药 治疗神经毒剂引起的SE，无论受害者的年龄如何。然而，有足够的 有证据表明，地西泮没有良好的神经保护作用，而且，在发育中的大脑中， 可能会加重SE引起的损伤。因此，需要动物数据来提供关于如何 保护未成熟的大脑免受神经毒剂暴露的损害，考虑到GABAA 受体介导的活动在发育中的大脑中可以是兴奋性的，而多巴胺能活动和 特别是NMDA受体的活性，其在兴奋性毒性中的作用是众所周知的， 宣布我们已经证明了LY 293558，一种AMPA/GluK 1受体拮抗剂， 停止癫痫发作，并显着减少神经病理学和长期缺陷的成年大鼠暴露于 索曼我们还测试了LY 293558与caramiphen的组合，caramiphen是一种具有NMDA的抗毒蕈碱剂 受体拮抗特性，并发现其终止梭曼诱导的癫痫发作比LY 293558更快 单独使用，在检查的所有脑区域中提供了对神经元损伤的完全保护，并且恢复了脑损伤。 动物是敏捷的，没有体重减轻。在本申请中，我们提出测试和比较以下的功效： LY 293558+卡拉米芬与单独LY 293558的组合，以及与两种苯二氮卓类药物地西泮和 咪达唑仑，对抗梭曼，在出生后7、12和21天的雄性和雌性大鼠中;抗惊厥药 在梭曼暴露后1小时进行治疗。我们假设LY 293558 +caramiphen将 提供比单独使用LY 293558更多的益处，并且将被证明远远上级地西泮和咪达唑仑 在阻止梭曼诱导的癫痫发作，防止神经元变性，神经元丢失，GABA能 杏仁核和海马的神经元间损失、萎缩和病理生理学改变，以及 认知、行为和神经功能缺陷研究长达6个月后。获取的数据将 在制定保护婴儿生命的安全和有效对策方面作出巨大贡献， 儿童和预防长期发病。