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

年龄和性别对神经毒剂对大脑的损害和解毒疗法的影响

• 批准号: 7669817
• 负责人: Edson X Albuquerque
• 金额: $ 9.87万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669817
• 关键词: Acetylcholine; Acetylcholinesterase; Acute; Address; Adult; Affect; Aftercare; Age; Alzheimer' s Disease; Animal Model; Animals; Antidotes; Atropine; Autoradiography; Behavior; Biological Assay; Blood; Brain; Butyrylcholinesterase; Cavia; Chemical Weapons; Cholinesterases; Clinical Research; Cognitive; Collaborations; Data; Dependency; Development; Dose; Drug Formulations; Drug Kinetics; Effectiveness; Enzymes; Erythrocytes; Event; Exposure to; Extracellular Signal Regulated Kinases; Family suidae; Female; Foundations; Galantamine; General Population; Glutamates; High Pressure Liquid Chromatography; Human; Immunohistochemistry; Impairment; Insecticides; Intoxication; Intramuscular Injections; Invasive; Lethal Dose 50; Long-Term Potentiation; Magnetic Resonance Imaging; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Muscarinic Antagonists; Neonatal; Neurons; Neurotransmitters; Organophosphorus Compounds; Pharmaceutical Preparations; Plasma; Poisoning; Primates; Research Personnel; Respiratory Diaphragm; Safety; Sarin; Slice; Soman; Surface; Sus scrofa; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Time; Toxic effect; Toxicokinetics; Treatment Effectiveness; Western Blotting; Whole Blood; base; cognitive function; emergency service responder; inhibitor/antagonist; male; morphometry; nerve agent; neuronal excitability; neurophysiology; novel; prevent; programs; response; sex; subcutaneous; synaptic function; tabun; tool; transmission process; white matter

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.

神经毒剂索曼、沙林和 VX 是与化学相关的有机磷化合物 (OP)，但 比OP杀虫剂毒性大得多。它们的大部分急性毒性来自不可逆的抑制 乙酰胆碱酯酶（AChE），一种使内源性神经递质乙酰胆碱失活的酶。 OP 中毒现有疗法的局限性已得到广泛认可，并且需要更有效的解毒剂 必须被开发。在这个项目中，我们将测试中心假设，即解毒疗法组成 加兰他敏是一种目前被批准用于治疗阿尔茨海默病 (AD) 的药物，无论有或没有 毒蕈碱拮抗剂阿托品可以抵消几内亚神经毒剂的即时和延迟毒性 不同年龄的雌雄猪。我们有证据表明加兰他敏和阿托品的组合， 在急性接触致死剂量的神经毒剂或杀虫剂之前或之后施用，有效 并安全地抵消其对青春期前后雄性豚鼠的毒性。尽管人们对他们知之甚少 神经生理学中，豚鼠被认为是预测神经生理学有效性的最佳非灵长类动物模型 人类OP中毒的解毒剂。在目标 1 中，我们将确定年龄和性别依赖性 索曼、沙林和VX的急性毒性，并优化由加兰他敏组成的解毒治疗， 或不含阿托品，适用于三个年龄段的雄性和雌性豚鼠，即新生儿、青春期前后和成年。这 优化治疗预防神经毒剂立即和/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 突触功能变化之间时间关系的治疗（电生理学研究）和 形态测定（非侵入性 MRI 研究）和神经元活力（组织病理学分析）的变化 豚鼠的大脑严重暴露于神经毒剂中。我们与 USAMRICD 研究人员合作 将进一步检查解毒疗法维持正常膈肌和认知能力的有效性 不同年龄暴露于神经毒剂的两性豚鼠的行为。在目标 3 中，我们将得出 拟议疗法安全性的后续临床研究所需的药代动力学参数 人类使用。仍然在这个目标范围内，我们将确定加兰他敏诱导的可逆抑制的相关性 不同区室中的 AChE 影响治疗的有效性。将特别强调 加兰他敏作为血液 AChE 的选择性抑制剂，将有助于清除 神经毒剂。在目标 4 中，我们将在整个动物水平上确定新颖的分子机制如何 有助于神经毒剂的毒性和加兰他敏/阿托品的有效性。这些结果 研究将具有深远的影响，因为它们将为加快开发安全解毒剂提供基础 供急救人员和普通人群在接触神经毒剂时使用。