Age and sex effects on nerve agent damage to the brain and antidotal therapies

神经毒剂梭曼、沙林和VX是化学上与之相关的有机磷化合物，但 比OP杀虫剂毒性更大。它们的急性毒性大部分来自于对 乙酰胆碱酯酶（AChE），使内源性神经递质乙酰胆碱失活的酶。 有效治疗OP中毒的局限性是众所周知的， 必须开发。在这个项目中，我们将测试的中心假设，解毒疗法组成 加兰他敏是目前批准用于治疗阿尔茨海默病（AD）的药物， 毒蕈碱拮抗剂阿托品可对抗神经毒剂的即刻和延迟毒性 不同年龄的猪。我们有证据证明加兰他敏和阿托品的组合， 在急性暴露于致命剂量的神经毒剂或杀虫剂之前或之后施用， 并在青春期前后的雄性豚鼠中安全地抵消它们的毒性。虽然对他们的情况知之甚少， 神经生理学，豚鼠被认为是最好的非灵长类动物模型，以预测的有效性 人类OP中毒的解毒剂。在目标1中，我们将确定 梭曼、沙林和VX的急性毒性，并优化由加兰他敏组成的解毒疗法， 或不含阿托品，用于三个年龄（即新生儿、青春期前后和成年）的雄性和雌性豚鼠。的 优化治疗预防神经毒剂的即刻和/或延迟毒性作用的有效性 然后将检查神经元功能和大脑完整性。在目标2中，我们将研究 治疗突触功能变化之间的时间关系（电生理研究）， 形态测量学（非侵入性MRI研究）和神经元活力（组织病理学分析）的改变， 急性暴露于神经毒剂的豚鼠大脑。与USAMRICD研究人员合作，我们 将进一步检查解毒治疗对维持正常膈肌和认知功能的有效性。 在不同年龄暴露于神经毒剂的雄性和雌性豚鼠的行为。在目标3中，我们将导出 后续拟定治疗安全性临床研究所需的药代动力学参数 人类使用。仍然在这个目标内，我们将确定加兰他敏诱导的可逆抑制的相关性， 的乙酰胆碱酯酶在不同的隔室治疗的有效性。将特别强调 认为加兰他敏作为血液AChE的选择性抑制剂， 神经毒剂在目标4中，我们将确定，在整个动物水平上， 有助于神经毒剂的毒性和加兰他敏/阿托品的有效性。的结果予以 研究将具有深远意义，因为它们将为加速开发安全解毒剂提供基础 供第一反应者和一般人群在暴露于神经毒剂的情况下使用。

The nerve agents soman, sarin and VX are organophosphorus compounds (OPs) chemically related to, but far more toxic than OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the endogenous neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes have to be developed. In this project, we will test the central hypothesis that an antidotal therapy composed of galantamine, a drug presently approved for treatment of Alzheimer's disease (AD), with or without the muscarinic antagonist atropine can counteract the immediate and delayed toxicity of nerve agents in guinea pigs of both sexes at different ages. We have evidence that the combination of galantamine and atropine, administered before or after an acute exposure to lethal doses of nerve agents or insecticides, effectively and safely counteracts their toxicity in peripubertal male guinea pigs. Although little is known regarding their neurophysiology, guinea pigs are considered the best non-primate model to predict the effectiveness of antidotes against OP intoxication in humans. In aim 1, we will determine the age and sex dependencies of the acute toxicity of soman, sarin, and VX, and optimize the antidotal therapy consisting of galantamine, with or without atropine, for male and female guinea pigs at three ages, i.e.neonatal, peripubertal, and adult. The effectiveness of the optimized therapy to prevent immediate and/or delayed toxic effects of the nerve agents will then be examined in neuronal function and brain integrity. In aim 2, we will investigate the effects of the therapy on the temporal relationship between changes in synaptic function (electrophysiological studies) and alterations in morphometry (non-invasive MRI studies) and neuronal viability (histopathological analysis) in the brains of guinea pigs acutely exposed to nerve agents. In collaboration with USAMRICD researchers, we will further examine the effectiveness of the antidotal therapy to maintain normal diaphragm and cognitive behavior in guinea pigs of both sexes exposed to nerve agents at different ages. In aim 3, we will derive pharmacokinetic parameters needed for subsequent clinical studies of the safety of the proposed therapy for human use. Still within this aim, we will determine the relevance of galantamine-induced reversible inhibition of AChE in distinct compartments to the effectiveness of the therapy. Particular emphasis will be given to the notion that galantamine, acting as a selective inhibitor of blood AChE, will facilitate the clearance of the nerve agents. In aim 4, we will determine, at whole animal level, how novel molecular mechanisms contribute to the toxicity of nerve agents and the effectiveness of galantamine/atropine. The results of these studies will be far reaching as they will provide the foundation to expedite the development of safe antidotes to be used by the first responders and the general population in the event of an exposure to nerve agents.