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: 7224647
• 负责人: Maria F. Braga
• 金额: $ 42.37万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224647
• 关键词: amygdala; brain; hippocampus; neuropathology; pilocarpine; play; role

DESCRIPTION (provided by applicant): Nerve agents are organophosphates with high toxicity, whose primary action is the irreversible inhibition of acetylcholinesterase. Clinical manifestations following nerve-agent exposure include the development of convulsive seizures, which can cause profound brain damage, resulting in death, or long-term cognitive deficits. At present, there are no prophylactic treatments that can effectively protect against nerve agent induced seizures, without causing significant side effects. Currently available post-exposure treatments can prevent death, but their efficacy in preventing seizures and associated brain damage has not been satisfactory. After exposure to a nerve agent, seizures are initiated primarily due to hyper-stimulation of muscarinic receptors. Cholinergic hyper-stimulation triggers glutamatergic hyperactivity, which intensifies and sustains seizures, and is ultimately responsible for neuronal damage. Therefore, anti-glutamatergic agents can be effective against seizures induced by cholinergic hyper-stimulation. Indeed, recent discoveries in the function of GluR5 kainate receptors (GluR5KRs, a kainate subtype of glutamate receptors containing the GluR5 subunit) have revealed that blockade of these receptors blocks epileptic seizures induced by the muscarinic agonist pilocarpine. As there are common mechanisms between pilocarpine-induced seizures and seizures induced by nerve agents, we hypothesize that antagonists of GluR5KRs will also be effective against nerve agent-induced seizures. The animal model we propose to use to test our hypothesis is in vivo exposure of rats to soman, as well as in vitro exposure of rat amygdala and hippocampal slices to soman. The selective GluR5KR antagonists LY293558 and UBP302 will be administered as a prophylactic treatment before exposure to soman, or as a therapy at different time points post-exposure. The efficacy of these antagonists against seizures will be correlated with their efficacy in preventing brain pathology, as well as pathophysiological alterations in the amygdala and hippocampus, studied in vitro after in vivo exposure to soman. The in vitro experiments will be performed in the amygdala and hippocampus because these brain regions play a pivotal role in the generation of brain seizures, including seizures induced by nerve agents. Furthermore, GluR5KRs play an important role in the regulation of neuronal excitability in the hippocampus, as well as in the amygdala, where we have found that strong activation of GluR5KRs inhibits evoked GABA release, and induces epileptiform activity. Because antagonists of GluR5KRs do not affect normal synaptic transmission, and the distribution of GluR5KRs in the brain is relatively limited, treatment with GluR5KR antagonists is likely to produce minimal or no side effects. Thus, the proposed investigations may result in the development of a novel, safe and effective prophylactic and/or therapeutic treatment against nerve agent-induced brain damage that will enhance our treatment response capabilities during an emergency.

性状（由申请方提供）：神经性毒剂是一种毒性很高的有机磷类毒剂，其主要作用是不可逆地抑制乙酰胆碱酯酶。神经毒剂暴露后的临床表现包括发生惊厥性癫痫发作，可引起严重的脑损伤，导致死亡或长期认知缺陷。目前，还没有预防性治疗可以有效地防止神经毒剂诱导的癫痫发作，而不会引起显着的副作用。目前可用的暴露后治疗可以预防死亡，但其在预防癫痫发作和相关脑损伤方面的效果并不令人满意。暴露于神经毒剂后，癫痫发作主要是由于毒蕈碱受体的过度刺激而引发的。胆碱能过度刺激触发海马能过度活动，这加剧并维持癫痫发作，并最终导致神经元损伤。因此，抗胆碱能药物可有效对抗由胆碱能过度刺激诱导的癫痫发作。事实上，最近在GluR 5红藻氨酸受体（GluR 5 KRs，含有GluR 5亚基的谷氨酸受体的红藻氨酸亚型）的功能中的发现已经揭示了阻断这些受体阻断由毒蕈碱激动剂毛果芸香碱诱导的癫痫发作。由于毛果芸香碱诱导的癫痫发作和神经毒剂诱导的癫痫发作之间存在共同的机制，我们假设GluR 5 KRs的拮抗剂也将有效对抗神经毒剂诱导的癫痫发作。我们建议使用的动物模型来测试我们的假设是在体内暴露的大鼠梭曼，以及在体外暴露的大鼠杏仁核和海马脑片梭曼。选择性GluR 5 KR拮抗剂LY 293558和UBP 302将在暴露于梭曼之前作为预防性治疗或在暴露后不同时间点作为治疗施用。这些拮抗剂抗癫痫发作的功效将与它们在体内暴露于梭曼后在体外研究的预防脑病理学以及杏仁核和海马体中的病理生理学改变的功效相关。体外实验将在杏仁核和海马体中进行，因为这些脑区在脑癫痫发作（包括神经毒剂诱导的癫痫发作）的产生中起关键作用。此外，GluR 5 KRs在海马和杏仁核中神经元兴奋性的调节中起重要作用，在杏仁核中，我们发现GluR 5 KRs的强烈激活抑制诱发的GABA释放，并诱导癫痫样活动。因为GluR 5 KRs的拮抗剂不影响正常的突触传递，并且GluR 5 KRs在脑中的分布相对有限，所以用GluR 5 KRs拮抗剂治疗可能产生最小的副作用或不产生副作用。因此，拟议的调查可能会导致开发一种新的，安全和有效的预防和/或治疗神经毒剂诱导的脑损伤的治疗，这将提高我们在紧急情况下的治疗反应能力。