Efficacy of GluR5 Antogonists Against Soman-Induced Seizures and Neuropathology

描述（由申请人提供）：目前，公民和政府官员都在考虑使用化学或生物毒素/武器对平民或部署在海外的军队进行恐怖袭击的可能性。神经毒剂是一种致命的化学武器，曾在战争和恐怖袭击中使用，造成了毁灭性的后果。暴露于神经毒剂的临床表现之一是癫痫发作和癫痫持续状态，可导致死亡，或脑损伤，造成长期认知/行为后果。这项应用的最终目标是开发一种针对神经毒剂的医疗对策，有效地阻止癫痫发作，防止脑损伤和由此导致的行为缺陷，并且没有显著的急性和/或长期不利影响。抗惊厥药物的一个新兴的有希望的靶标是含有GluR5亚基（GluRSKRs）的盐酸盐受体类型。我们已经在成年雄性大鼠中证明了GluRSKR拮抗剂对索曼诱导的癫痫发作和神经病理的疗效。在拟议的研究中，将在未成熟、成年和老年雄性和雌性大鼠中测试GluR5KR/AMPA拮抗剂LY293558和GluRSKR拮抗剂UBP302对索曼诱导的癫痫发作、神经病理学、病理生理学和由此导致的认知/行为缺陷的疗效。这些GluRSKR拮抗剂的安全性/毒性研究也是该申请的一部分。在人体暴露24小时、1周、1个月和3个月后，使用基于设计的立体学方法研究杏仁核、海马体和前额叶皮层的神经元丢失和神经退行性变。这些大脑区域的神经元兴奋性和突触可塑性（长期增强）的改变以及行为缺陷将在人体暴露后1和3个月进行研究。在认知和情绪过程中起关键作用的大脑区域，行为与神经病理学和病理生理学的相关性将为somman诱导的认知/行为缺陷的机制提供有价值的信息，以及LY293S58和UBP302在预防或减少这些缺陷方面的有效性。

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.