Identification of novel therapeutic approaches for TETS and OP intoxication

描述（由申请人提供）：灭鼠剂四亚甲基二硫四胺（TETS）和有机磷农药对硫磷（OP）被认为是可靠的恐怖主义威胁剂。目前针对急性TETS或OP中毒的医疗对策可以预防死亡，但不能充分保护中枢神经系统免受持续癫痫发作和/或永久性损伤。因此，必须制定新的和更有效的对策，以便在接触急性毒性水平的TETS、对硫磷和类似化学威胁剂后，为平民、急救人员和军事人员提供更好的医疗。本研究的目标是建立TETS和对硫磷诱发癫痫发作的啮齿动物模型，然后利用这些模型确定潜在的治疗药物。我们寻求确定可以防止癫痫发作的发展或治疗癫痫发作一旦他们已经开始和/或可以防止不可逆的神经元损伤的药物。我们计划评估2,3-苯二氮卓类AMPA受体拮抗剂和可溶性环氧化物水解酶抑制剂（sEHi）。我们最近的研究表明，AMPA受体拮抗剂提供持续的癫痫发作保护，并且在对地西泮（通常用于治疗急性TETS和OP中毒的苯二氮卓类药物）有难治性的后期给药时能够阻止癫痫发作。我们和其他人的数据表明，sEHi也表现出抗癫痫的特性。也许更重要的是，鉴于最近的证据表明，抗炎化合物与标准解毒剂联合使用可显著减少急性OP中毒的神经元损伤，我们已经证明sEHi也是有效的抗炎化合物。这些观察结果表明，AMPA受体拮抗剂和sEHi可能通过延长治疗窗口和增强神经保护，显著改善急性TETS和对硫磷中毒的临床管理。为了验证这一假设，我们将解决两个具体目标：(1)建立急性TETS和对硫磷中毒的啮齿动物模型；2)确定AMPA受体拮抗剂和/或sEHi在暴露于化学威胁剂之前或之后是否对急性TETS或对硫磷中毒有治疗作用。将在所有Aims中测量的终点包括发病时间、慢性和强直性癫痫发作的频率和持续时间、脑电图、神经病理学的组织学测量和TETS、AMPA受体拮抗剂和sEHi的血液水平。AMPA受体拮抗剂和sEHi目前正在进行人体临床试验，并证明了良好的安全性记录；这将有助于将这些啮齿动物模型的积极发现转化为人类研究。总之，该项目将开发急性TETS和对硫磷中毒的啮齿动物模型，这将对拟议研究之外的领域有用，并将为两种不同类型的化学威胁剂提供具有实用价值的新治疗方法的关键信息。

DESCRIPTION (provided by applicant): The rodenticide tetramethylenedisulfotetramine (TETS) and the organophosphorus (OP) pesticide parathion are considered credible terrorist threat agents. Current medical countermeasures for acute TETS or OP intoxication can prevent mortality but do not sufficiently protect the CNS from persistent seizures and/or permanent injury. Therefore, new and more effective countermeasures must be developed to facilitate better medical treatment of civilians, first responders and military personnel following exposure to acutely toxic levels of TETS, parathion and similar chemical threat agents. The goals of the proposed research are to develop rodent models of TETS- and parathion-induced seizures and then use these models to identify potential therapeutic agents. We seek to identify agents that can protect against the development of seizures or treat seizures once they have begun and/or can prevent irreversible neuronal injury. We plan to evaluate a 2,3- benzodiazepine AMPA receptor antagonist and a soluble epoxide hydrolase inhibitor (sEHi). We have recently shown that AMPA receptor antagonists provide sustained seizure protection and are able to block seizures when administered at later times when there is refractoriness to diazepam, the benzodiazepine typically used to treat acute TETS and OP intoxication. We and others have data indicating that sEHi also exhibit anti- epileptic properties. Perhaps more important in light of recent evidence suggesting that the use of anti- inflammatory compounds in combination with standard antidote significantly decreases neuronal damage in acute OP intoxication, we have demonstrated that sEHi are also potent anti-inflammatory compounds. These observations suggest the potential for AMPA receptor antagonists and sEHi to significantly improve the clinical management of acute TETS and parathion intoxication by extending the therapeutic window and enhancing neuroprotection. To test this hypothesis, we will address two specific aims: (1) Develop rodent models of acute TETS and parathion intoxication; and 2) Determine whether AMPA receptor antagonist and/or sEHi are of therapeutic benefit in acute TETS or parathion intoxication when administered prior to or after exposure to the chemical threat agent. Endpoints that will be measured across all Aims include time to onset, frequency and duration of clonic and tonic seizures, EEG, histological measures of neuropathology and blood levels of TETS, AMPA receptor antagonist and sEHi. AMPA receptor antagonists and sEHi are currently undergoing human clinical trials and have demonstrated an excellent safety record; which will facilitate translation of positive findings in these rodent models to human studies. In summary, this project will develop rodent models of acute TETS and parathion intoxication that will be useful to the field beyond the proposed studies, and it will generate critical information on novel treatment approaches of practical value for two diverse classes of chemical threat agents. PUBLIC HEALTH RELEVANCE: The rodenticide tetramethylenedisulfotetramine (TETS) and the organophosphorus (OP) pesticide parathion are considered credible terrorist threat agents. Current medical countermeasures for acute TETS or OP intoxication can prevent mortality but do not sufficiently protect the CNS from persistent seizures and/or permanent injury. The goal of this research project is to test the hypothesis that AMPA receptor antagonists and/or inhibitors of soluble epoxide hydrolases will significantly improve outcome following exposure to acutely toxic levels of TETS and parathion by extending the therapeutic window for seizure protection and enhancing neuroprotection.