Efficacy of GluR5 Antogonists Against Soman-Induced Seizures and Neuropathology

GluR5 拮抗剂对梭曼诱发的癫痫发作和神经病理学的功效

• 批准号: 8145354
• 负责人: Maria F. Braga
• 金额: $ 52.64万
• 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: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145354
• 关键词: Acute; Adult; Adverse effects; Amygdaloid structure; Anticonvulsants; Behavior; Behavioral; Biological; Brain Injuries; Brain region; Cessation of life; Chemical Weapons; Chemicals; Clinical; Cognitive; Development; Effectiveness; Emergency Situation; Emotional; Event; Exposure to; Female; Functional disorder; Goals; Government Officials; Hippocampus (Brain); Hour; Kainic Acid Receptors; Lead; Long-Term Potentiation; Medical; Military Personnel; Mind; Morbidity - disease rate; Nerve Degeneration; Play; Prefrontal Cortex; Process; Rattus; Safety; Seizures; Soman; Staining method; Stains; Status Epilepticus; Synaptic plasticity; Testing; Toxic effect; Toxin; Vulnerable Populations; War; aged; base; design; fluoro jade; male; mortality; nerve agent; neuron loss; neuronal excitability; neuropathology; pre-clinical; prevent; public health relevance; weapons

DESCRIPTION (provided by applicant): The possibility of a terrorist attack with chemical or biological toxins/weapons against civilians, or military troops deployed overseas is at present in the minds of both citizens and government officials. Nerve agents are lethal chemical weapons that have been used in war and in terrorist attacks, with devastating consequences. One of the clinical manifestations of exposure to nerve agents is seizure activity and status epilepticus which can lead to death, or brain damage with long-term cognitive/behavioral consequences. The ultimate goal of this application is the development of a medical countermeasure against nerve agents that will effectively stop seizures and protect from brain damage and the resulting behavioral deficits, and do so without significant acute and/or long-term adverse effects. An emerging promising target for anticonvulsant drugs is the type of kainate receptors that contains the GluR5 subunit (GluRSKRs). We have already shown the efficacy of GluRSKR antagonists against soman-induced seizures and neuropathology in adult male rats. In the proposed studies, the efficacy of LY293558, a GluR5KR/AMPA antagonist, and UBP302, a GluRSKR antagonist will be tested against soman-induced seizures, neuropathology, pathophysiology, and the resulting cognitive/behavioral deficits in immature, adult, and aged male and female rats. Safety/toxicity studies of these GluRSKR antagonists are also part of this application. Neuronal loss, using design-based stereology, and neurodegeneration, using Fluoro-Jade-C staining will be studied in the amygdala, hippocampus, and prefrontal cortex, at 24 hours, 1 week, 1 month, and 3 months after soman exposure. Alterations in neuronal excitability and synaptic plasticity (long-term potentiation) in these brain regions, and behavioral deficits will be investigated at 1 and 3 months after soman exposure. The correlation of behavior with neuropathology and pathophysiology in brain regions that play a key role in cognitive and emotional processes will provide valuable information regarding the mechanisms underlying soman-induced cognitive/behavioral deficits, and the effectiveness of LY293S58 and UBP302 in preventing or minimizing these deficits. Public Health Relevance: These studies will provide the preclinical information necessary to determine if GluRSKR antagonists can be effectively and safely used against nerve agents in an emergency situation to protect the people. Including a section of the particularly vulnerable population, and will result in the development of new compounds that will reduce mortality and morbidity during and after an emergency event involving nerve agents.

描述（由申请人提供）：目前公民和政府官员都担心，针对平民或部署在海外的军队使用化学或生物毒素/武器进行恐怖袭击的可能性。神经毒剂是致命的化学武器，曾在战争和恐怖袭击中使用，造成毁灭性后果。接触神经毒剂的临床表现之一是癫痫发作和癫痫持续状态，这可能导致死亡或脑损伤，并产生长期认知/行为后果。该应用的最终目标是开发针对神经毒剂的医学对策，该措施将有效阻止癫痫发作并防止脑损伤和由此产生的行为缺陷，并且不会产生明显的急性和/或长期不良影响。抗惊厥药物的一个新兴有希望的靶标是含有 GluR5 亚基 (GluRSKR) 的红藻氨酸受体类型。我们已经在成年雄性大鼠中展示了 GluRSKR 拮抗剂对梭曼诱发的癫痫发作和神经病理学的功效。在拟议的研究中，将在未成熟、成年和老年男性中测试 LY293558（一种 GluR5KR/AMPA 拮抗剂）和 UBP302（一种 GluRSKR 拮抗剂）针对梭曼诱发的癫痫发作、神经病理学、病理生理学以及由此产生的认知/行为缺陷的功效和雌性老鼠。这些 GluRSKR 拮抗剂的安全性/毒性研究也是本申请的一部分。将在暴露于梭曼后 24 小时、1 周、1 个月和 3 个月时，使用基于设计的体视学研究神经元损失，并使用 Fluoro-Jade-C 染色研究杏仁核、海马和前额叶皮层的神经变性。这些大脑区域的神经元兴奋性和突触可塑性（长期增强）的变化以及行为缺陷将在梭曼暴露后 1 个月和 3 个月进行研究。行为与在认知和情绪过程中发挥关键作用的大脑区域的神经病理学和病理生理学的相关性将提供有关梭曼引起的认知/行为缺陷的潜在机制的有价值的信息，以及LY293S58和UBP302在预防或最小化这些缺陷方面的有效性。 公共卫生相关性：这些研究将提供必要的临床前信息，以确定 GluRSKR 拮抗剂是否可以在紧急情况下有效且安全地用于对抗神经毒剂以保护人民。包括一部分特别脆弱的人群，并将导致新化合物的开发，从而降低涉及神经毒剂的紧急事件期间和之后的死亡率和发病率。