Developmental neurotoxicity of sarin and soman in guinea pigs

沙林和索曼对豚鼠的发育神经毒性

• 批准号: 8337702
• 负责人: Edson X Albuquerque
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337702
• 关键词: Acetylcholine; Acetylcholinesterase; Acute; Adult; Age; Alzheimer' s Disease; Animal Behavior; Animal Model; Animal Testing; Antidotes; Anxiety; Atropine; Behavior; Behavioral; Birds; Birth; Brain; Brain region; Carboxylic Ester Hydrolases; Cavia; Chemicals; Chlorpyrifos; Cognitive; Cognitive deficits; Data; Development; Diazinon; Dose; Drug usage; Effectiveness; Electroencephalogram; Emotional; Enzymes; Epidemiologic Studies; Event; Exposure to; Fetus; Functional disorder; Galantamine; Goals; Histopathology; Human; Impaired cognition; Intoxication; Knowledge; Lead; Magnetic Resonance Imaging; Medical; Metabolic; Metabolism; Modeling; Monitor; Motor; Mus; Muscarinic Acetylcholine Receptor; National Institute of Neurological Disorders and Stroke; Neonatal; Neuraxis; Neurologic; Neurons; Organophosphorus Compounds; Perinatal Exposure; Pesticides; Pharmaceutical Preparations; Poisoning; Population; Pregnancy; Pregnant Women; Rattus; Readiness; Reporting; Research; Safety; Saline; Sarin; Soman; Spectrum Analysis; Structure; Subcutaneous Injections; Subway; Testing; Therapeutic; Therapeutic Intervention; Tokyo; Toxic effect; behavior test; brain electrical activity; carboxylesterase; clinically relevant; developmental neurotoxicity; medical attention; multidisciplinary; nerve agent; neurobehavior; neurobehavioral; neurobehavioral test; neuropathology; nonhuman primate; offspring; postnatal; pregnant; prenatal exposure; prepuberty; prevent; programs; social; synaptogenesis; toxicant; translational study; young adult

DESCRIPTION (provided by applicant): The sensitivity of the developing mammalian central nervous system (CNS) to organophosphorus (OP) nerve agents and the safety of antidotes such as atropine and pralidoxime, commonly used against acute OP toxicity, in pregnant women and the developing fetuses are hitherto unknown. Thus, during the 1995 terrorist attack with sarin in the Tokyo subway, pregnant women who sought medical attention after presenting mild signs of OP intoxication received no therapeutic treatment. The urgency of studies to investigate the developmental neurotoxicity of OP nerve agents is underscored by the recent report of the neurobehavioral teratogenicity of sarin in an avian model. In recent years, galantamine, a drug currently approved to treat Alzheimer's disease, emerged as an effective antidote against acute OP poisoning in neonatal, prepubertal, and adult guinea pigs. Treatment with galantamine was also shown to counteract the cognitive deficits and anxiety-like behavior seen months after a single exposure of prepubertal guinea pigs to 0.6-1.0xLD50 soman. The present project is, therefore, aimed at testing the central hypothesis that the developing mammalian CNS is exquisitely sensitive to the nerve agents sarin and soman and that galantamine or atropine will be effective medical countermeasures against the developmental neurotoxicity of these agents. The guinea pig will be the animal model of choice because: (i) brain development of guinea pigs closely resembles that of humans and non-human primates and (ii) like humans, guinea pigs have low levels of circulating carboxylesterases - the enzymes that metabolically inactivate OP compounds. The immediate goals of this project are: (i) to identify the effects of a prenatal exposure to soman or sarin on neurobehavior as well as functional, structural, and metabolic integrity of the brain of guinea pigs, and (ii) to assess the safety and effectiveness of galantamine or atropine, at doses that are compatible with human use, to counter the developmental toxicity of the nerve agents. Pregnant guinea pigs will receive, at a critical gestational period (GD 50-52), a subcutaneous injection of vehicle or a given dose (0.6x or 1.0xLD50) of soman or sarin. Subsequently (1 or 24 h later), the sows will be treated with saline (0.5 ml/kg, im) or a clinically relevant dose of galantamine (8 mg/kg, im) o atropine (0.5 mg/kg, im). On postnatal days 35-40 (prepuberty) and 120-125 (young adulthood), cognitive and emotional behavior of the animals will be analyzed. To examine the effects of the prenatal exposure to the nerve agents on electrical brain activity, electroencephalographic activity will be telemetrically monitored prior to the behavioral tests. Magnetic resonance imaging and spectroscopy will be used to identify deviations in brain structure and metabolism. The results of these translational, multidisciplinary studies will be far reaching as they will laythe groundwork necessary to advance research aimed at identifying safe and effective therapeutic strategies to treat even the most sensitive sector of the population in the event of a terrorist attack with sarin and soman.

描述（由申请人提供）：发育中的哺乳动物中枢神经系统（CNS）对有机磷（OP）神经毒剂的敏感性以及解毒剂（如阿托品和解磷定）的安全性，这些解毒剂通常用于治疗孕妇和发育中的急性有机磷中毒。胎儿至今仍未知。因此，在 1995 年东京地铁沙林恐怖袭击期间，出现轻微 OP 中毒症状后就医的孕妇没有得到任何治疗。最近关于沙林在禽类模型中神经行为致畸性的报告强调了研究 OP 神经毒剂的发育神经毒性研究的紧迫性。近年来，加兰他敏（一种目前被批准用于治疗阿尔茨海默病的药物）成为针对新生儿、青春期前和成年豚鼠急性OP中毒的有效解毒剂。加兰他敏治疗也被证明可以抵消青春期前豚鼠单次暴露于 0.6-1.0xLD50 索曼几个月后出现的认知缺陷和焦虑样行为。因此，本项目旨在检验以下中心假设：发育中的哺乳动物中枢神经系统对神经毒剂沙林和梭曼极其敏感，加兰他敏或阿托品将是针对这些毒剂的发育神经毒性的有效医学对策。豚鼠将成为首选动物模型，因为：(i) 豚鼠的大脑发育与人类和非人类灵长类动物的大脑发育非常相似，并且 (ii) 与人类一样，豚鼠的循环羧酸酯酶水平较低，循环羧酸酯酶是代谢过程中的酶。使 OP 化合物失活。该项目的近期目标是：（i）确定产前接触梭曼或沙林对豚鼠大脑神经行为以及功能、结构和代谢完整性的影响，以及（ii）评估 加兰他敏或阿托品的安全性和有效性，其剂量与人类使用相容，以对抗神经毒剂的发育毒性。怀孕的豚鼠将在关键妊娠期（GD 50-52）接受皮下注射媒介物或给定剂量（0.6x 或 1.0xLD50）的梭曼或沙林。随后（1或24小时后），用盐水（0.5ml/kg，肌肉注射）或临床相关剂量的加兰他敏（8mg/kg，肌肉注射）或阿托品（0.5mg/kg，肌肉注射）治疗母猪。在出生后 35-40 天（青春期前）和 120-125 天（成年早期），将对动物的认知和情感行为进行分析。为了检查产前接触神经毒剂对脑电活动的影响，将在行为测试之前对脑电图活动进行遥测监测。磁共振成像和光谱学将用于识别大脑结构和新陈代谢的偏差。这些转化性、多学科研究的结果将具有深远的影响，因为它们将为推进研究奠定必要的基础，旨在确定安全有效的治疗策略，以在发生沙林和索曼恐怖袭击时治疗最敏感的人群。 。