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）神经剂的敏感性以及在孕妇和发育中的急性OP毒性中使用的解毒剂（如阿托品和pralidoxime）的安全性，如急性OP毒性胎儿迄今未知。因此，在1995年在东京地铁上与沙林的恐怖袭击中，在提出轻度OP中毒迹象后寻求医疗护理的孕妇没有治疗治疗。最近在禽类模型中，Sarin神经行为致神经性的报道强调了研究术语神经毒剂的发育神经毒性的紧迫性。近年来，Galantamine是一种目前被批准治疗阿尔茨海默氏病的药物，它是一种有效的解毒剂，可在新生儿，青春期前和成年豚鼠中对急性OP中毒。甘氨酸的治疗也被证明可以抵消后几个月在单次前豚鼠暴露于0.6-1.0xld50 soman后几个月看到的认知缺陷和焦虑样行为。因此，本项目的目的是检验中心假设，即发育中的哺乳动物中枢神经系统对神经剂Sarin和Soman非常敏感，而Galantamine或Atropine将是针对这些药物发育神经毒性的有效医学对策。豚鼠将成为首选的动物模型，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相似，并且（ii）像人类一样，豚鼠的循环羧酸酯酶水平较低 - 酶的酶 - 代谢上的酶灭活OP化合物。该项目的直接目标是：（i）确定对索曼或沙林的暴露对神经行为的影响以及豚鼠大脑大脑的功能，结构和代谢完整性，以及（ii）评估 甘氨酸或阿托品的安全性和有效性，与人类使用兼容的剂量，以应对神经剂的发育毒性。怀孕的豚鼠将在关键的妊娠期（GD 50-52）接受皮下注射媒介物或给定剂量（0.6倍或1.0XLD50）的SOMAN或SARIN。随后（1或24小时后），母猪将用盐水（0.5 mL/kg，IM）或临床相关剂量的甘氨酸（8 mg/kg，IM）O阿托品（0.5 mg/kg，IM）治疗。在产后第35-40天（预伯蒂）和120-125（成年年轻），将分析动物的认知和情感行为。为了检查产前暴露于神经剂对电脑活动的影响，将在行为测试之前对脑电图活性进行远程监测。磁共振成像和光谱法将用于确定大脑结构和代谢中的偏差。这些翻译，多学科研究的结果将是遥不可及的，因为它们将为促进研究所必需的基础，以识别安全有效的治疗策略，即使在恐怖袭击萨林和索曼的情况下，甚至对治疗人口中最敏感的部门也是对待人口中最敏感的部门。