Identification of novel therapeutic approaches for TETS and OP intoxication

说明(申请人提供)：杀鼠剂毒鼠强(TETS)和有机磷(OP)杀虫剂对硫磷被认为是可靠的恐怖威胁物质。目前对急性TETS或OP中毒的医学对策可以防止死亡，但不能充分保护中枢神经系统免受持续性癫痫发作和/或永久性损伤。因此，必须制定新的更有效的对策，以促进平民、急救人员和军事人员在暴露于剧毒水平的TETS、对硫磷和类似的化学威胁剂后得到更好的医疗。这项拟议研究的目标是建立TETS和对硫磷诱导的癫痫发作的啮齿动物模型，然后使用这些模型来识别潜在的治疗剂。我们寻求确定能够防止癫痫发作的发展或一旦癫痫发作开始治疗和/或能够防止不可逆转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)。我们最近证明，AMPA受体拮抗剂提供持续的癫痫保护，并能够阻止癫痫发作，当安定无效时再给药，安定是一种苯二氮类药物，通常用于治疗急性TETS和OP中毒。我们和其他人的数据表明，sEHI也显示出抗癫痫的特性。也许更重要的是，鉴于最近有证据表明，抗炎化合物与标准解毒剂联合使用显著减少了急性OP中毒时神经元的损伤，我们证明了sEHI也是有效的抗炎化合物。这些观察表明，AMPA受体拮抗剂和sEHI有可能通过延长治疗窗口和加强神经保护来显著改善急性TETS和对硫磷中毒的临床治疗。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；以及(2)确定AMPA受体拮抗剂和/或sEHI在急性TETS或对硫磷中毒中使用时，在暴露于化学威胁剂之前或之后是否具有治疗益处。将在所有目标上测量的终点包括发作时间、阵挛和强直发作的频率和持续时间、脑电图、神经病理的组织学指标以及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，并已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阳性发现转化为人体研究。综上所述，该项目将开发急性TETS和对硫磷中毒的啮齿动物模型，这些模型将在拟议的研究之外对该领域有用，并将产生关于对两种不同类别的化学威胁剂具有实用价值的新治疗方法的关键信息。 公共卫生相关性：杀鼠剂毒鼠强(TETS)和有机磷(OP)农药对硫磷被认为是可靠的恐怖主义威胁物剂。目前对急性TETS或OP中毒的医学对策可以防止死亡，但不能充分保护中枢神经系统免受持续性癫痫发作和/或永久性损伤。本研究项目的目的是验证AMPA受体拮抗剂和/或可溶性环氧化物水解酶抑制剂将通过延长癫痫保护的治疗窗口和加强神经保护而显著改善暴露于急性毒性水平的TETS和对硫磷后的结局的假说。

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.