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.

神经毒剂是曾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。目前，大规模接触神经毒剂的风险非常高。其中一位临床医生 急性暴露于神经毒剂的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。针对有毒物质的医学对策势在必行 神经毒剂的作用被开发出来并可用，它不仅可以拯救生命，还可以保护 防止长时间SE引起的脑损伤，以及随之而来的长期疾病。目前，安定 DZP是FDA批准的用于治疗神经毒剂诱发的SE及其替代品的抗惊厥药物 咪达唑仑(MDZ)正在考虑中。然而，有充分的证据表明，两者都不是 苯二氮卓类药物具有良好的抗癫痫和神经保护作用。因此，一种更有效的 需要治疗来取代DZP和MDZ。我们已经完成了大量的研究工作 梭曼暴露的大鼠，证明AMPA/GluK1受体拮抗剂LY293558(Tezampanel)施加 与DZP或MDZ相比，抗癫痫和神经保护效果要好得多。然而，我们也 发现暴露6个月后(对大鼠的寿命来说很长)，即使是LY293558治疗的大鼠 提出了脑损伤的证据，表明诱导的神经病理具有进行性。 这表明了长期研究在评估抗惊厥剂的神经保护效果方面的重要性。 因此，为了增强神经保护效果，我们随后测试了LY293558与 NMDA受体拮抗剂--我们使用了卡米芬，这是一种具有NMDA受体拮抗剂的抗心肌梗死药 特性--在接触梭曼后长达6个月的时间里，发现了对大脑损伤的完全保护。多数 这些研究都是在幼鼠(出生后第21天或第12天)中进行的。当前的目标是 应用LY293558+卡米芬在成年雄性和雌性大鼠身上进行试验，以完成所有的 将这种高效的联合疗法引导到晚期阶段所需的临床前研究 发展。我们将把老年大鼠包括在拟议的研究中，以便获得与以下相关的临床前数据 老年人口，这是更难保护的。将与接触梭曼的大鼠进行比较 用MDZ治疗。抗惊厥药物将在接触梭曼后1小时给予，以模拟 大规模接触的真实情况，即不太可能立即获得医疗服务。我们的中央 假设LY293558+卡拉米芬在控制梭曼诱导的作用方面远优于MDZ 癫痫发作，防止神经元变性，神经元丢失，GABA能神经元间丢失，萎缩和 杏仁核和海马体的病理生理变化，核磁共振显示的整体脑病理， 以及神经学(自发性反复发作的发展-癫痫的发生)和行为 (焦虑样行为增加)异常，研究长达6个月后暴露。

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