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

基本信息

批准号：
7681582
负责人：
Maria F. Braga
金额：
$ 43.23万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681582
关键词：
AMPA Receptors Acetylcholine Acetylcholinesterase Acute Adverse effects Affect Amygdaloid structure Animal Model Animals Anticonvulsants Area Behavioral Brain Brain Injuries Brain Pathology Brain region Cell Nucleus Cells Cessation of life Chemicals Clinical Cognitive Cognitive deficits Conflict (Psychology)Development Doctor of Dental Surgery Doctor of Philosophy Emergency Situation Epilepsy Exposure to Functional disorder Generations GluR5 kainate receptor Glutamate Receptor Glutamatergic Agents Glutamates Hippocampus (Brain)Histologic Hour Hyperactive behavior In Vitro International Investigation Kainic Acid Receptors Knowledge Mediating Medical Military Personnel Monitor Motor Seizures Muscarinic Acetylcholine Receptor Muscarinic Agonists Neuraxis Neurologic Neurons Neuroprotective Agents Organophosphates Organophosphorus Compounds Oxidative Stress Pilocarpine Play Poisoning Prophylactic treatment Rattus Regulation Research Personnel Role Seizures Slice Soman Subcutaneous Injections Synaptic Transmission Techniques Testing Therapeutic Time Toxic effect Treatment Effectiveness behavior observation cholinergic cognitive function efficacy testing excitotoxicity extracellular gamma-Aminobutyric Acid in vitro activity in vivo interest kainate nerve agent neuron loss neuronal excitability neuropathology novel patch clamp prevent programs prophylactic receptor research study response transmission process treatment response

项目摘要

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（申请人提供）：神经毒剂是具有高毒性的有机磷酸酯，其主要作用是不可逆地抑制乙酰胆碱酯酶。接触神经毒剂后的临床表现包括发生惊厥性癫痫发作，这可能会导致严重的脑损伤，从而导致死亡或长期认知缺陷。目前，尚无预防性治疗可以有效预防神经毒剂引起的癫痫发作，且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，但其预防癫痫发作和相关脑损伤的功效并不令人满意。接触神经毒剂后，癫痫发作主要是由于毒蕈碱受体的过度刺激而引发。胆碱能过度刺激会引发谷氨酸能过度活跃，从而加剧和维持癫痫发作，并最终导致神经元损伤。因此，抗谷氨酸药物可以有效对抗胆碱能过度刺激引起的癫痫发作。事实上，最近对 GluR5 红藻氨酸受体（GluR5KR，一种含有 GluR5 亚基的谷氨酸受体的红藻氨酸亚型）功能的发现表明，阻断这些受体可以阻止由毒蕈碱激动剂毛果芸香碱诱导的癫痫发作。由于毛果芸香碱诱发的癫痫发作和神经毒剂诱发的癫痫发作之间存在共同机制，因此我们假设 GluR5KR 拮抗剂也能有效对抗神经毒剂诱发的癫痫发作。我们建议用来检验我们的假设的动物模型是大鼠体内暴露于梭曼，以及大鼠杏仁核和海马切片体外暴露于梭曼。选择性GluR5KR拮抗剂LY293558和UBP302将作为暴露于梭曼之前的预防性治疗，或作为暴露后不同时间点的治疗。这些拮抗剂抗癫痫发作的功效将与其预防脑病理学以及杏仁核和海马体病理生理学改变的功效相关，这是在体内暴露于梭曼后进行的体外研究。体外实验将在杏仁核和海马体中进行，因为这些大脑区域在脑癫痫发作（包括神经毒剂诱发的癫痫发作）的产生中发挥着关键作用。此外，GluR5KRs 在海马和杏仁核神经元兴奋性的调节中发挥着重要作用，我们发现 GluR5KRs 的强烈激活会抑制诱发的 GABA 释放，并诱导癫痫样活动。因为GluR5KR拮抗剂不影响正常的突触传递，并且GluR5KR在大脑中的分布相对有限，所以用GluR5KR拮抗剂治疗可能产生最小的副作用或没有副作用。因此，所提出的研究可能会导致开发出一种新颖、安全且有效的针对神经毒剂引起的脑损伤的预防和/或治疗方法，这将增强我们在紧急情况下的治疗反应能力。