Antiglutamatergic Therapy to Protect the Brain Against Nerve Agents

抗谷氨酸治疗可保护大脑免受神经毒剂的侵害

• 批准号: 10685433
• 负责人: Maria F. Braga
• 金额: $ 74.93万
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685433
• 关键词: Acetylcholinesterase; Acute; Adult; Advanced Development; Amygdaloid structure; Anticonvulsants; Anxiety; Appearance; Applications Grants; Atrophic; Behavioral; Benzodiazepines; Brain; Brain Injuries; Brain Pathology; Caring; Cessation of life; Chemical Weapons; Clinical; Combined Modality Therapy; Communication; Data; Deterioration; Development; Diazepam; Drug Kinetics; Effectiveness; Elderly; Electroencephalography; Epileptogenesis; Exposure to; FDA approved; Female; Funding; Glutamates; Goals; Grant; Hippocampus; Interneurons; Joints; Lead; Legal patent; Licensure; Longevity; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medical; Midazolam; Military Personnel; Morbidity - disease rate; Muscarinics; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; National Institute of Allergy and Infectious Disease; Nature; Nerve Degeneration; Neurologic; Organophosphorus Compounds; Peripheral; Population; Property; Rattus; Recurrence; Research; Risk; Seizures; Soman; Status Epilepticus; Survival Rate; Synaptic Transmission; Technology Transfer; Terrorism; Testing; Time; Toxic effect; War; Work; aged; antagonist; anxiety-like behavior; chemical threat; cholinergic; cost; efficacious treatment; efficacy evaluation; excitotoxicity; male; medical countermeasure; nerve agent; neuron loss; neuropathology; neuroprotection; postnatal; pre-clinical; pre-clinical research; prevent; receptor; receptor internalization; young adult

Nerve agents are lethal chemical weapons that have been used in war and terrorist attacks, with devastating consequences. The risk for mass exposure to nerve agents is presently very high. One of the clinical manifestations of acute exposure to nerve agents is seizure activity progressing to status epilepticus (SE), which can lead to death, or brain damage. It is imperative that medical countermeasures against the toxic effects of nerve agents are developed and become available, which will not only save lives, but also protect against brain damage caused by prolonged SE, and the ensuing long-term morbidities. Currently, diazepam (DZP) is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam (MDZ) is under consideration. There is ample evidence, however, indicating that neither benzodiazepine has satisfactory antiseizure and neuroprotective efficacy. Therefore, a more efficacious therapy is needed to replace DZP and MDZ. We have already completed a significant amount of research in soman-exposed rats, demonstrating that an AMPA/GluK1 receptor antagonist, LY293558 (tezampanel), exerts a far superior antiseizure and neuroprotective efficacy in comparison with DZP or MDZ. However, we also found that 6 months after exposure (a long time for the life span of a rat), even LY293558-treated rats presented evidence of brain damage, suggesting a progressive nature of the induced neuropathology, and indicating the importance of long-term studies in evaluating the neuroprotective efficacy of an anticonvulsant. Therefore, to enhance neuroprotective efficacy, we subsequently tested the combination of LY293558 with an NMDA receptor antagonist—we used caramiphen, an antimuscarinic with NMDA receptor antagonistic properties—and found complete protection against brain damage up to 6 months after soman exposure. Most of these studies have been conducted in young rats (postnatal day 21 or 12). The goal of the present application is to test LY293558+caramiphen in adult male and female rats, in order to complete all the preclinical research necessary to lead this highly efficacious combination therapy to the stage of advanced development. We will include aged rats in the proposed studies, in order to obtain preclinical data pertinent to the elderly population, which is more difficult to protect. Comparisons will be made with soman-exposed rats treated with MDZ. The anticonvulsants will be administered at 1 h after soman exposure in order to simulate a real case scenario of mass exposure, when medical care is unlikely to available immediately. Our central hypothesis is that LY293558+caramiphen will prove to be far superior to MDZ in controlling soman-induced seizures, preventing neuronal degeneration, neuronal loss, GABAergic interneuronal loss, atrophy and pathophysiological alterations in the amygdala and hippocampus, overall brain pathology as revealed by MRI, as well as neurological (development of spontaneous recurrent seizures – epileptogenesis) and behavioral (increased anxiety-like behavior) abnormalities, studied up to 6 months postexposure.

神经因子是在战争和恐怖袭击中使用的致命化学武器，毁灭性的 结果。大量暴露于神经药物的风险很高。临床之一 急性暴露于神经剂的表现是癫痫活性发展为癫痫持续状态（SE），， 必须对有毒的医学对策 神经毒剂的影响是开发和可用的，这不仅可以挽救生命，还可以保护 反对长时间的SE造成的脑损伤以及随之而来的长期病毒。目前，地西ep （DZP）是FDA批准的抗惊厥药，用于治疗神经剂诱导的SE及其更换 咪达唑仑（MDZ）正在考虑。但是，有足够的证据表明 苯二氮卓类药物具有令人满意的抗性和神经保护效果。因此，更有效 需要治疗来替代DZP和MDZ。我们已经完成了大量的研究 暴露于Soman的大鼠，证明AMPA/GLUK1受体拮抗剂LY293558（Tezampanel）执行 与DZP或MDZ相比，与抗性和神经保护效率相比得多。但是，我们也是如此 发现暴露后6个月（大鼠的寿命长时间），甚至是LY293558治疗的大鼠 提供了脑损伤的证据，表明诱发神经病理学的渐进性 表明长期研究在评估抗惊厥药的神经保护效率方面的重要性。 因此，为提高神经保护效率，我们随后测试了LY293558与 NMDA受体拮抗剂 - 我们使用Caramiphen，一种与NMDA受体拮抗作用 属性 - 发现在SOMAN暴露后长达6个月内完全保护脑损伤。最多 这些研究已经在年轻大鼠（产后第21天或第12天）进行。现在的目标 应用是在成年雄性和雌性大鼠中测试LY293558+caramiphen，以完成所有 将这种高效的组合疗法带到高级阶段所必需的临床前研究 发展。我们将在拟议的研究中包括老年大鼠，以获取与 老年人口更难保护。比较将与暴露于Soman的大鼠进行 用MDZ处理。抗惊厥药将在Soman暴露后1小时内给予，以模拟 当医疗服务不太可能立即可用时，大规模暴露的真实情况。我们的中心 假设是LY293558+caramiphen在控制索曼诱导的时将被证明要比MDZ优越得多 癫痫发作，预防神经元变性，神经元丧失，GABA能丧失，萎缩和 杏仁核和海马的病理生理改变，MRI揭示的总体脑病理学， 以及神经系统（赞助复发性癫痫发作 - 癫痫发生）和行为 （动画样的行为增加）异常，在暴露后长达6个月研究。

项目成果

Alpha-linolenic acid enhances the facilitation of GABAergic neurotransmission in the BLA and CA1.

α-亚麻酸增强 BLA 和 CA1 中 GABA 能神经传递的促进。

• DOI: 10.1177/15353702231165010
• 发表时间: 2023
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Pidoplichko,VolodymirI;Figueiredo,TaizaH;Braga,MariaFm;Pan,Hongna;Marini,AnnM
• 通讯作者: Marini,AnnM

Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition.

• DOI: 10.3390/toxics11100866
• 发表时间: 2023-10-18
• 期刊: Toxics
• 影响因子: 4.6
• 作者: Aroniadou-Anderjaska V;Figueiredo TH;de Araujo Furtado M;Pidoplichko VI;Braga MFM
• 通讯作者: Braga MFM

Acute and long-term consequences of exposure to organophosphate nerve agents in humans.

• DOI: 10.1111/epi.14500
• 发表时间: 2018-10
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Figueiredo TH;Apland JP;Braga MFM;Marini AM
• 通讯作者: Marini AM