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.

描述（由申请人提供）：神经剂是具有高毒性的有机磷酸盐，其主要作用是对乙酰胆碱酯酶的不可逆转抑制。神经药物暴露后的临床表现包括发育性癫痫发作，这会导致严重的脑损伤，导致死亡或长期认知缺陷。目前，尚无预防治疗可以有效地保护神经剂诱发的癫痫发作，而不会引起明显的副作用。目前可用的暴露后治疗可以预防死亡，但是它们在预防癫痫发作和相关脑损伤方面的功效并不令人满意。暴露于神经剂后，癫痫发作主要是由于毒蕈碱受体的过度刺激。胆碱能过度刺激会触发谷氨酸能多动症，从而增强和维持癫痫发作，并最终导致神经元损伤。因此，抗谷氨酸能剂可以有效地抵抗胆碱能过度刺激引起的癫痫发作。实际上，最近在GlUR5海藻酸盐受体（Glur5krs，含有GlUR5亚基的谷氨酸受体的海藻酸盐亚型）功能方面发现的发现，这些受体的阻断阻断了这些受体的阻塞阻塞由肌肉碱性的促毒药引起的癫痫发作。由于在神经剂诱导的毛果石诱导的癫痫发作和癫痫发作之间存在共同的机制，因此我们假设Glur5krs的拮抗剂也将有效地针对神经剂诱导的癫痫发作。我们建议用于检验假设的动物模型是大鼠在体内暴露于Soman，以及大鼠杏仁核和海马切片的体外暴露于Soman。选择性GLUR5KR拮抗剂LY293558和UBP302将在暴露于SOMAN之前作为预防治疗，或在暴露后不同时间点进行治疗。这些拮抗剂对癫痫发作的疗效将与它们在预防脑病理学方面的功效以及杏仁核和海马的病理生理改变相关，并在体内暴露于soman后体外研究了体外。体外实验将在杏仁核和海马中进行，因为这些大脑区域在脑癫痫发作的产​​生中起着关键作用，包括神经剂诱导的癫痫发作。此外，GLUR5KRS在海马中以及杏仁核中的神经元兴奋性的调节中起着重要作用，在那里我们发现GLUR5KRS的强激活抑制了引起的GABA释放，并诱导癫痫表现活性。由于GlUR5KR的拮抗剂不影响正常的突触传播，并且Glur5KR在大脑中的分布相对有限，因此用GlUR5KR拮抗剂的治疗可能会产生最小或无副作用。因此，拟议的研究可能导致开发针对神经剂诱导的脑损伤的新型，安全有效的预防性和/或治疗治疗，这将增强我们在紧急情况下的治疗反应能力。