Developmental neurotoxicity of sarin and soman in guinea pigs

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，以及通常用于孕妇和发育中的胎儿的解毒剂（如阿托品和普拉多肟）的安全性迄今尚不清楚。因此，在1995年东京地铁沙林毒气恐怖袭击期间，出现轻微OP中毒症状后求医的孕妇没有得到治疗。研究OP神经毒剂的发育性神经毒性的紧迫性，最近的报告强调了沙林在鸟类模型中的神经行为致畸性。近年来，加兰他明，一种目前被批准用于治疗阿尔茨海默病的药物，作为一种有效的解毒剂，出现在新生儿、青春期前和成年豚鼠的急性OP中毒中。用加兰他明治疗也被证明可以抵消认知缺陷和焦虑样行为，这是在青春期前的豚鼠单次暴露于0.6-1.0 ld50索曼几个月后出现的。因此，本项目旨在验证一个中心假设，即发育中的哺乳动物中枢神经系统对神经毒剂沙林和索曼非常敏感，而加兰他明或阿托品将是对抗这些毒剂的发育神经毒性的有效医学对策。豚鼠将成为动物模型的选择，因为：(i)豚鼠的大脑发育与人类和非人类灵长类动物非常相似；（ii）与人类一样，豚鼠的循环羧酸酯酶水平较低，这种酶可以在代谢过程中使OP化合物失活。该项目的直接目标是：(1)确定产前暴露于索曼或沙林对豚鼠神经行为以及大脑功能、结构和代谢完整性的影响，以及(2)评估

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. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to provide fundamental and timely input for assessment of the developmental toxicity of the nerve agents soman and sarin and identification of lead compounds for adequate treatment of neuropathologies that result from prenatal exposure to these agents.