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: 7743917
• 负责人: Edson X Albuquerque
• 金额: $ 7.5万
• 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/7743917
• 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; 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; 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.

神经剂Soman，Sarin和VX是与化学相关的有机磷化合物（OPS），但 比OP杀虫剂更具毒性。他们的大多数急性毒性是由于不可逆转的抑制作用 乙酰胆碱酯酶（ACHE），是使内源性神经递质乙酰胆碱失活的酶。 可用疗法对OP中毒的局限性已得到充分认识，并且更有效的解毒剂 必须开发。在这个项目中，我们将检验一个中心假设，即构成的解毒疗法 Galantamine是一种目前批准治疗阿尔茨海默氏病（AD）的药物，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直接和延迟毒性 两性猪在不同年龄。我们有证据表明，甘氨酸和阿托品的结合， 在急性暴露于致命剂量的神经剂或杀虫剂之前或之后，有效地给药 并安全地抵消了它们在叶叶伯氏雄性豚鼠中的毒性。虽然对他们的 神经生理学，几内亚猪被认为是预测有效性的最佳非青睐模型 对人类中的OP中毒的解毒剂。在AIM 1中，我们将确定 索曼，沙林和VX的急性毒性，并优化由甘氨酸组成的解毒疗法 或没有阿托品，对于三个年龄的雄性和雌性豚鼠，即否定，peri骨和成人。这 优化疗法的有效性，以防止神经剂的立即和/或延迟毒性作用 然后将在神经元功能和大脑完整性中进行检查。在AIM 2中，我们将研究 治疗突触功能变化（电生理研究）和 形态计量学的改变（非侵入性MRI研究）和神经元生存力（组织病理学分析） 豚鼠的大脑急性暴露于神经剂。与USAMRICD研究人员合作，我们 将进一步研究解毒疗法维持正常隔膜和认知的有效性 两性豚鼠的行为在不同年龄暴露于神经毒剂上。在AIM 3中，我们将得出 随后对拟议治疗安全性的临床研究所需的药代动力学参数 人使用。仍在此目标范围内，我们将确定甘氨酸诱导的可逆抑制的相关性 在疗法有效性的不同隔室中的疼痛。特别强调 甘兰胺（充当血液疼痛的选择性抑制剂）的观念将有助于清除 神经毒剂。在AIM 4中，我们将在整个动物水平上确定新型分子机制 有助于神经剂的毒性和甘氨酸/阿托品的有效性。这些结果 研究将遥不可及，因为它们将为加快安全解毒的发展提供基础 在暴露于神经药物的情况下，第一反应者和一般人群使用。