Organophosphate Action in the Central Nervous System

有机磷在中枢神经系统中的作用

• 批准号: 7667195
• 负责人: Neil Marc Nathanson
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667195
• 关键词: Acetylcholinesterase Inhibitors; Adrenergic Agents; Adrenergic Agonists; Agonist; Agriculture; Animals; Brain; Brain region; Cause of Death; Cell Death; Cessation of life; Convulsions; Dopamine; Environmental Exposure; Enzymes; Epilepsy; Exposure to; Genetic; Heterozygote; Human; In Vitro; Intervention; Japan; Knock-out; Knockout Mice; Lead; Mediating; Molecular; Molecular Genetics; Molecular Mechanisms of Action; Mouse Strains; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinic Antagonists; Muscarinic M1 Receptor; Mutant Strains Mice; Nervous System Physiology; Nervous system structure; Neuraxis; Neurologic; Neurons; Norepinephrine; Organophosphates; Paraoxon; Pathway interactions; Patients; Peripheral; Pesticides; Pharmacotherapy; Phase; Pilocarpine; Play; Population; Predisposition; Preparation; Prevention; Receptor Activation; Receptor Gene; Research; Resistance; Role; Sarin; Seizures; Slice; Staging; Stimulation of Cell Proliferation; Subgroup; System; Testing; Therapeutic Uses; Toxic effect; Ventilatory Depression; Viral; Work; adrenergic; cell injury; cholinergic; human CHRM1 protein; improved; inhibitor/antagonist; insight; nerve agent; neurochemistry; neurogenesis; neuron loss; noradrenergic; organophosphate poisoning; precursor cell; prevent; public health relevance; receptor; relating to nervous system; research study; toxic organophosphate insecticide exposure

DESCRIPTION (provided by applicant): Organophosphate (OP) acetylcholinesterase inhibitors are used widely in agriculture as pesticides and also have been used in terrorist attacks against civilian populations. OPs are irreversible acetylcholinesterase inhibitors which can cause death due to overstimulation of both central and peripheral cholinergic systems. Overstimulation of muscarinic acetylcholine receptors (mAChR) in the central nervous system (CNS) can cause respiratory depression and convulsions. This research will use genetic, pharmacological, and molecular approaches to define underlying mechanisms of OP action in the CNS and to identify new pharmacological targets to prevent or ameliorate OP-induced actions in the CNS. OP-induced seizures progress through three neurochemical stages: an initial phase which can be blocked by muscarinic antagonists, followed by a transitional period where both cholinergic and noncholinergic pathways contribute to the seizures, and followed by mainly noncholinergic-mediated seizure activity. This proposal will use mouse strains deleted of specific mAChR genes to determine the subtype of receptor which mediates OP-induced convulsions. This proposal will also use pharmacological and genetic approaches to determine the roles of the noradrenergic and dopaminergic systems and their receptors in OP-induced seizures. Prevention and/or termination of OP- induced seizure activity is critical both for reduction of rapid lethality and pathological neurological changes. The cell damage after OP-induced seizures is followed by proliferation of neuronal precursor cells. This increased neurogenesis has been suggested to both contribute to and to limit the long-term damage caused by OP exposure. This proposal will also determine the mechanisms and contributions of convulsive and non- convulsive pathways to OP-induced cell death and neurogenesis. Environmental exposure to OP pesticides causes thousands of death world-wide. The dangers of the use of OP nerve agents in attacks on civilian populations was demonstrated by the sarin attacks in Japan in 1994 and 1995 which resulted not only in immediate deaths but in changes in long-lasting neurological functions. This research will provide valuable new insights into the mechanisms of OP action in the CNS and identify new potential targets for specific pharmacological interventions to ameliorate the effects of OP on the CNS. PUBLIC HEALTH RELEVANCE Organophosphates are inhibitors of the nervous system enzyme acetylcholinesterase inhibitors and are used widely in agriculture as pesticides and also have been used in terrorist attacks against civilian populations. Exposure to organophosphates can cause convulsions and long-term damage to the central nervous system. This research will determine the molecular mechanism for these actions and may identify targets for improved treatment of organophosphate poisoning.

描述（由申请人提供）： 有机磷酸酯（OP）乙酰胆碱酯酶抑制剂作为杀虫剂广泛用于农业，并且还被用于针对平民的恐怖袭击。 OP 是不可逆的乙酰胆碱酯酶抑制剂，可因过度刺激中枢和外周胆碱能系统而导致死亡。中枢神经系统 (CNS) 中毒蕈碱乙酰胆碱受体 (mAChR) 的过度刺激可导致呼吸抑制和抽搐。这项研究将使用遗传、药理学和分子方法来定义 OP 在中枢神经系统中作用的潜在机制，并确定新的药理学靶点来预防或改善 OP 诱导的中枢神经系统作用。 OP 诱导的癫痫发作经历三个神经化学阶段：可以被毒蕈碱拮抗剂阻断的初始阶段，随后是胆碱能和非胆碱能途径均有助于癫痫发作的过渡期，最后是主要非胆碱能介导的癫痫发作活动。该提案将使用删除特定 mAChR 基因的小鼠品系来确定介导 OP 诱导的惊厥的受体亚型。该提案还将使用药理学和遗传学方法来确定去甲肾上腺素能和多巴胺能系统及其受体在 OP 诱发的癫痫发作中的作用。预防和/或终止 OP 诱发的癫痫发作对于减少快速致死率和病理性神经学变化至关重要。 OP 引起的癫痫发作后细胞受损，随后神经元前体细胞增殖。这种神经发生的增加被认为有助于并限制OP暴露造成的长期损害。该提案还将确定惊厥和非惊厥途径对 OP 诱导的细胞死亡和神经发生的机制和贡献。环境中暴露于有机磷农药导致全世界数千人死亡。 1994 年和 1995 年日本发生的沙林毒气袭击事件证明了使用 OP 神经毒剂攻击平民的危险性，这些袭击不仅导致立即死亡，而且导致长期神经功能发生变化。这项研究将为OP在中枢神经系统中的作用机制提供有价值的新见解，并确定特定药理干预的新潜在靶点，以改善OP对中枢神经系统的影响。公众健康相关性 有机磷酸酯是神经系统酶乙酰胆碱酯酶抑制剂的抑制剂，在农业中广泛用作杀虫剂，也被用于针对平民的恐怖袭击。接触有机磷酸酯会导致抽搐并对中枢神经系统造成长期损害。这项研究将确定这些作用的分子机制，并可能确定改善有机磷中毒治疗的目标。