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 母亲和胎儿的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 (AChE) 然而，尽管治疗干预导致了自发流产、婴儿和/或孕产妇死亡， 产后神经系统并发症（包括癫痫和认知缺陷）可能会持续存在，尽管很少见。 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 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) 药物的药理学特征。 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，THP 抑制 M1 和 M3 此外，THP 还抑制尚未识别的神经元亚型。 胎盘中烟碱型乙酰胆碱受体 (nAChR) 过度激活 M1/M3 mAChR 和神经元 nAChR。 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 因此，该项目将部分检验以下假设： 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。 毒死蜱 (CPF)，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 恐怖袭击的多学科方法、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 1 和 2 将确定 THP 在拯救生命、减少污染方面的有效性。 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 CPF 的目标 3 将揭示导致这一现象的机制。 CPF的毒性和THP的解毒功效的研究的成功完成将奠定该项目的基础。 为开发更有效的解毒剂来治疗妊娠期间急性 CPF 中毒奠定了基础。 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，它还解决了一个未得到满足的问题。 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

Postnatal Guinea Pig Brain Development, as Revealed by Magnetic Resonance and Diffusion Kurtosis Imaging.

磁共振和扩散峰度成像显示出生后豚鼠大脑发育。

• 发表时间: 2020-06-12
• 影响因子: 3.3
• 作者: Mullins, Roger J;Xu, Su;Zhuo, Jiachen;Roys, Steve;Pereira, Edna F R;Albuquerque, Edson X;Gullapalli, Rao P
• 通讯作者: Gullapalli, Rao P

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

妊娠期接触有机磷杀虫剂：从急性中毒到发育神经毒性。

• 发表时间: 2020
• 影响因子: 4.7
• 作者: Todd, Spencer W;Lumsden, Eric W;Aracava, Yasco;Mamczarz, Jacek;Albuquerque, Edson X;Pereira, Edna F R
• 通讯作者: Pereira, Edna F R

(R,S)-trihexyphenidyl, acting via a muscarinic receptor-independent mechanism, inhibits hippocampal glutamatergic and GABAergic synaptic transmissions: Potential relevance for treatment of organophosphorus intoxication.

(R,S)-trihexyphenidyl 通过毒蕈碱受体独立机制发挥作用，抑制海马谷氨酸能和 GABA 能突触传递：与有机磷中毒治疗的潜在相关性。

• 发表时间: 2023-11-15
• 影响因子: 4.7
• 作者: Aracava, Yasco;Albuquerque, Edson X;Pereira, Edna F R
• 通讯作者: Pereira, Edna F R

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

产前暴露于低浓度有机磷杀虫剂马拉硫磷的青春期前豚鼠的学习和记忆保留缺陷。

• 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