Targeting M1/M3 Muscarinic Receptors to Treat Gestational Pesticide Poisoning

靶向 M1/M3 毒蕈碱受体治疗妊娠期农药中毒

• 批准号: 10320743
• 负责人: RAO P GULLAPALLI
• 金额: $ 53.14万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320743
• 关键词: Acetylcholine; Acetylcholinesterase; Acute; Address; Aftercare; Age; Agonist; Amygdaloid structure; Animal Model; Animals; Anti-Inflammatory Agents; Antidotes; Atropine; Behavioral; Brain; Cavia; Cells; Chemicals; Chlorpyrifos; Cholinergic Receptors; Cognitive deficits; Corpus striatum structure; Dependence; Development; Dose; Dystonia; Effectiveness; Electroencephalography; Enzyme-Linked Immunosorbent Assay; Equilibrium; Exposure to; Feedback; Female; Fetal health; Fetus; Frequencies; Health; Hippocampus (Brain); Histologic; Immunohistochemistry; Inflammation; Intoxication; Life; Light; Magnetic Resonance Imaging; Maternal Health; Maternal Mortality; Medical; Microglia; Monitor; Morbidity - disease rate; Mothers; Muscarinic Acetylcholine Receptor; Muscarinic M2 Receptor; Muscarinic M3 Receptor; Nervous system structure; Neuroglia; Neurologic; Neurons; Nicotinic Receptors; Oral; Outcome; Parkinson Disease; Pattern; Persons; Pesticides; Pharmaceutical Preparations; Pharmacology; Placebo Control; Placenta; Poison; Poisoning; Population; Pregnancy; Prevention; Public Health; Randomized; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk Assessment; Security; Seizures; Spontaneous abortion; Telemetry; Terrorism; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Ultrasonography; World Health Organization; acute toxicity; antagonist; behavior test; blind; channel blockers; chemical threat; cholinergic; cholinergic neuron; cognitive development; cognitive function; compare effectiveness; cytokine; density; design; effective therapy; fetal; improved; in vivo; infant death; interdisciplinary approach; male; methoctramine; mortality; myometrium; neuroinflammation; neurotoxicity; offspring; pesticide intoxication; pesticide poisoning; postnatal; postnatal development; pregnant; presynaptic; prevent; response; therapeutically effective; voltage

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.

抽象的 妊娠期间有机磷 (OP) 农药中毒对孕妇和婴儿来说都会危及生命 母亲和胎儿。治疗很大程度上依赖于使用高剂量的阿托品来阻断毒蕈碱 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，尽管治疗干预导致自然流产、婴儿和/或孕产妇死亡， 产后神经系统并发症（包括癫痫发作和认知缺陷）可能会随之而来。虽然很少 考虑到阿托品对所有毒蕈碱受体 (mAChR) 亚型的非选择性抑制可能 成为这些不良结果的重要决定因素。具体来说，抑制突触前 mAChR（主要是 M2）是限制胆碱能神经元释放乙酰胆碱的负反馈回路的一部分，可以 加剧 OP 引起的胆碱能危机。 R,S-苯海索 (THP) 药物的药理学概况 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病， 使其成为治疗妊娠期 OP 中毒的有吸引力的候选者。与阿托品相比，THP 更具选择性 与 M2 mAChR 相比，对 M1 和 M3 的抑制作用更大。此外，THP 还能抑制尚未确定的神经元亚型 烟碱型乙酰胆碱受体 (nAChR)。胎盘中 M1/M3 mAChR 和神经元 nAChR 过度激活 和子宫肌层以及心肺和神经系统可能导致不良的健康结果 妊娠期间发生急性 OP 中毒后。因此，该项目将检验以下假设： 除了 M1/M3 mAChR 之外，THP 还可以保护 M2 mAChR，并可能通过阻断 nAChR 治疗妊娠期 OP 中毒比阿托品更有效。重点将放在 毒死蜱 (CPF) 是一种广泛使用的 OP 农药，目前已纳入美国国土安全部 化学品威胁风险评估清单，其中列出了可能用于毒害大量人员的化学品 恐怖袭击。多学科方法、转化相关的动物模型（豚鼠）和 安慰剂对照、随机、盲法设计，最大限度地减少实验偏差并最大限度地提高科学严谨性 将用于实现三个目标。目标 1 和 2 将确定 THP 在拯救生命、减少 急性毒性迹象，并防止母亲和胎儿出现神经系统并发症 妊娠期暴露于高剂量的 CPF。目标 3 将阐明有助于实现这一目标的机制 CPF 的毒性和 THP 的解毒效果。该项目的顺利完成将为 为开发更有效的解毒剂来治疗妊娠期间急性 CPF 中毒奠定基础。 确定可以对人群健康结果产生积极影响的治疗干预措施 OP农药严重中毒者支持世界卫生组织解决这一问题的倡议 急性有机磷农药中毒问题，特别是在发展中国家。此外，它还完成了一个未满足的 对这些农药故意攻击的受害者进行有效治疗的医疗需求。

项目成果

Gestational exposures to organophosphorus insecticides: From acute poisoning to developmental neurotoxicity.

妊娠暴露于有机磷杀虫剂：从急性中毒到发育神经毒性。

• DOI: 10.1016/j.neuropharm.2020.108271
• 发表时间: 2020-12-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Todd SW;Lumsden EW;Aracava Y;Mamczarz J;Albuquerque EX;Pereira EFR
• 通讯作者: Pereira EFR

Learning and memory retention deficits in prepubertal guinea pigs prenatally exposed to low levels of the organophosphorus insecticide malathion.

• DOI: 10.1016/j.ntt.2020.106914
• 发表时间: 2020-09
• 期刊: Neurotoxicology and teratology
• 影响因子: 2.9
• 作者: Lumsden EW;McCowan L;Pescrille JD;Fawcett WP;Chen H;Albuquerque EX;Mamczarz J;Pereira EFR
• 通讯作者: Pereira EFR