Targeting M1/M3 Muscarinic Receptors to Treat Gestational Pesticide Poisoning

摘要 孕期有机磷农药中毒对双方都是一种危及生命的情况。 母亲和胎儿。治疗在很大程度上依赖于使用大剂量阿托品来阻断毒扁豆碱 OP诱导的乙酰胆碱酯酶阻断导致乙酰胆碱(ACh)受体过度激活 (疼痛)。然而，尽管进行了治疗干预，自发性流产、婴儿和/或产妇死亡， 而出生后的神经系统并发症(包括癫痫发作和认知障碍)可能随之而来。虽然很少 考虑到阿托品对所有M受体(MAChR)亚型的非选择性抑制作用，阿托品可能 是这些糟糕结果的一个重要决定因素。具体地说，对突触前mAChRs(主要是 M2)，它们是限制胆碱能神经元释放ACh的负反馈回路的一部分，可以 加重OP诱导的胆碱能危机。药物R，S-三己基苯啶的药理研究概况 该药物已在怀孕期间安全使用，并被批准用于治疗肌张力障碍和帕金森氏症， 使其成为治疗妊娠期OP中毒的有吸引力的候选药物。与阿托品相比，THP更有选择性 抑制M1和M3而不是M2的mAChRs。此外，THP还抑制迄今尚未确定的神经元亚型 烟碱型ACh受体(NAChRs)。胎盘M1/M3mAChRs和神经元型nAChRs的过度激活 和子宫肌层，以及在心肺和神经系统中，可能导致不良的健康结果 在怀孕期间发生急性有机磷农药中毒。因此，这个项目将检验这一假设，部分是通过 备用M2 mAChR，并可能通过阻止除M1/M3 mAChR之外的nAChR，THP将 在治疗妊娠期OP中毒方面比阿托品更有效。重点将放在 毒死蜱(CPF)，一种广泛使用的OP杀虫剂，目前包括在美国国土安全部 化学品威胁风险评估可能被部署以毒害大量人口的化学品清单 恐怖袭击。多学科方法，翻译相关的动物模型(豚鼠)，以及 安慰剂对照、随机、盲目设计，最大限度地减少实验偏差和最大限度地提高科学严谨性 将被用来解决三个目标。目标1和目标2将确立THP在拯救生命、减少 急性毒性的迹象，并防止母亲和胎儿出现神经系统并发症 孕期暴露在高剂量的CPF中。目标3将阐明导致 CPF的毒性和THP的解毒作用。该项目的成功完成将为 为开发更有效的解毒剂治疗妊娠期急性CPF中毒奠定了基础。 确定可对人群健康结果产生积极影响的治疗干预措施 对有机磷农药的极度沉迷支持了世界卫生组织应对 急性有机磷农药中毒问题，特别是在发展中国家。此外，它还实现了一个未满足的 对故意使用这些杀虫剂袭击的受害者进行有效治疗的医疗需要。

ABSTRACT Poisoning with organophosphorus (OP) pesticides during gestation is a life-threatening condition for both mothers and fetuses. Treatment relies heavily on the use of high doses of atropine to block muscarinic receptor overactivation by acetylcholine (ACh) build up due to OP-induced block of acetylcholinesterase (AChE). However, despite therapeutic intervention spontaneous miscarriages, infant and/or maternal deaths, and postnatal neurological complications (including seizures and cognitive deficits) can ensue. Although rarely taken into account, the non-selective inhibition of all muscarinic receptor (mAChR) subtypes by atropine may be an important determinant of these poor outcomes. Specifically, inhibition of presynaptic mAChRs (mostly M2), which are part of a negative feedback loop that limits ACh release from cholinergic neurons, can exacerbate the OP-induced cholinergic crisis. The pharmacological profile of R,S-trihexyphenidyl (THP), a drug that has been safely used during pregnancy and is approved for treatment dystonia and Parkinson’s disease, makes it an attractive candidate to treat gestational OP poisoning. In contrast to atropine, THP more selectively inhibits M1 and M3 than M2 mAChRs. In addition, THP inhibits as-of-yet unidentified subtypes of neuronal nicotinic ACh receptors (nAChRs). Overactivation of M1/M3 mAChRs and neuronal nAChRs in the placenta and myometrium, and in the cardiorespiratory and nervous systems can contribute to poor health outcomes following acute OP intoxication during pregnancy. Thus, this project will test the hypothesis that, in part by sparing M2 mAChRs and potentially by blocking nAChRs in addition to M1/M3 mAChRs, THP will be more potent and efficacious than atropine to treat gestational OP poisoning. The focus will be on chlorpyrifos (CPF), a widely used OP pesticide currently included in the U.S. Department of Homeland Security Chemical Threat Risk Assessment list of chemicals that may be deployed to poison large numbers of people in terrorist attacks. A multidisciplinary approach, a translationally relevant animal model (the guinea pig), and a placebo-controlled, randomized, blind design that minimizes experimental bias and maximizes scientific rigor will be used to address three aims. Aims 1 and 2 will establish the effectiveness of THP to save lives, reduce signs of acute toxicity, and prevent the development of neurological complications in mothers and fetuses gestationally exposed to a high dose of CPF. Aim 3 will shed light on the mechanisms that contribute to the toxicity of CPF and the antidotal effectiveness of THP. Successful completion of this project will lay the groundwork for the development of more effective antidotes to treat acute CPF intoxication during pregnancy. Identification of therapeutic interventions that can have a positive impact on the health outcomes of populations acutely intoxicated with OP pesticides lends support to the initiative of the World Health Organization to tackle the issue of acute OP pesticide intoxication, particularly in the developing world. In addition, it fulfills an unmet medical need for the effective treatment of victims of a deliberate attack with these pesticides.