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.

神经毒剂是在战争和恐怖袭击中使用的致命化学武器，具有毁灭性 后果；它们再次被用来对付平民的可能性目前很高。其中一个 暴露于神经毒剂的临床表现是癫痫活动进展到癫痫持续状态(SE) 这可能会导致死亡或脑损伤，并产生长期的神经和行为后果。这个 美国儿科学会指出了儿童可能更容易受到神经影响的原因 毒物毒性；然而，关于保护儿童的适当对策的信息很少。 人口，因为缺乏关于未成熟动物的数据。FDA已批准安定作为抗惊厥药物 治疗神经毒剂诱发的SE，无论受害者的年龄。然而，有足够的 证据表明，安定没有良好的神经保护效果，在发育中的大脑中，它 可能会加重SE造成的损伤。因此，需要动物数据来提供关于如何 在神经毒剂暴露的情况下保护未成熟的大脑免受损害，考虑到GABAA 受体介导的活性在发育中的大脑中是兴奋的，而谷氨酸能活性和 尤其是nmda受体的活性，它们在兴奋性毒性中的作用是众所周知的， 已经宣布了。我们已经证明了AMPA/GluK1受体拮抗剂LY293558在 染毒成年大鼠停止癫痫发作并显著降低神经病理学和长期功能缺陷 索曼。我们还测试了LY293558与卡米芬的联合用药，卡米芬是一种与NMDA一起使用的抗霉菌药物 受体拮抗特性，并发现它比LY293558更快地终止梭曼诱导的癫痫发作 单独使用时，可在所检查的所有脑区提供全面的保护，防止神经元损伤，并可恢复 动物跑得很快，体重没有减轻。在目前的应用中，我们建议测试和比较 LY293558+卡拉米芬与LY293558单用，并与两种苯二氮卓类药物安定和 咪达唑仑对出生后7、12和21天的雄性和雌性大鼠的抗梭曼作用；抗惊厥药 治疗将在接触梭曼1小时后进行。我们假设LY293558+卡拉米芬会 提供比LY293558更多的好处，并将被证明远远优于安定和咪达唑仑 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 杏仁核和海马区的神经元间丢失、萎缩和病理生理改变，以及 对暴露后6个月的认知、行为和神经缺陷进行了研究。所获得的数据将 为制定安全有效的婴儿和儿童生命保护对策作出巨大贡献 儿童和预防长期疾病。