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。神经毒剂是致命的化学武器，曾用于战争和恐怖袭击，造成毁灭性后果。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，并造成长期的认知/行为后果。本申请的最终目标是开发针对神经毒剂的医学对策，其将有效地阻止癫痫发作并保护免受脑损伤和由此产生的行为缺陷，并且这样做不会产生显著的急性和/或长期不良反应。抗惊厥药物的一个新兴的有希望的靶点是含有GluR 5亚基（GluRSKRs）的红藻氨酸受体类型。我们已经在成年雄性大鼠中显示了GluRSKR拮抗剂对梭曼诱导的癫痫发作和神经病理学的疗效。在拟定的研究中，将在未成熟、成年和老年雄性和雌性大鼠中测试LY 293558（GluR 5 KR/AMPA拮抗剂）和UBP 302（GluRSKR拮抗剂）对梭曼诱导的癫痫发作、神经病理学、病理生理学以及由此产生的认知/行为缺陷的疗效。这些GluRSKR拮抗剂的安全性/毒性研究也是本申请的一部分。在梭曼暴露后24小时、1周、1个月和3个月，使用基于设计的体视学研究杏仁核、海马和前额皮质中的神经元损失，使用Fluoro-Jade-C染色研究神经变性。在梭曼暴露后1个月和3个月，将研究这些脑区神经元兴奋性和突触可塑性（长时程增强）的变化以及行为缺陷。行为与在认知和情绪过程中起关键作用的脑区域中的神经病理学和病理生理学的相关性将提供关于梭曼诱导的认知/行为缺陷的潜在机制以及LY 293 S58和UBP 302在预防或最小化这些缺陷中的有效性的有价值的信息。

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.