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Soman-induced neuropathology in Gottingen minipig: large animal model assessment for MCM

哥廷根小型猪中梭曼诱导的神经病理学：MCM 的大型动物模型评估

基本信息

批准号：
9921503
负责人：
Lucille Lange
金额：
$ 15.4万
依托单位：
GENEVA FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921503
关键词：
Acute Age Anatomy Animal Model Animal Testing Alternatives Animals Antiepileptic Agents Astrocytes Atropine Behavioral Benzodiazepines Birth Intervals Brain Brain Pathology Cardiotoxicity Chemical Warfare Chemicals Confidence Intervals Data Development Diazepam Dose Ethics Experimental Models Exposure to FDA approved Future Goals Hippocampus (Brain)Human Intramuscular Lethal Dose 50 Litter Size Macaca mulatta Methods Microglia Military Personnel Miniature Swine Modeling Moods Natural History Neuroprotective Agents Pharmaceutical Preparations Physiology Poison Population Pregnancy Procedures Quarantine Refractory Research Rodent Model Sarin Seizures Soman Status Epilepticus Sulfate Time Toxic effect animal rule cost cyclosarin demographics drug efficacy human subject male medical countermeasure nerve agent neuroinflammation neuron loss neuronal survival neuropathology nonhuman primate novel predicting response response screening

项目摘要

It is important to comprehensively characterize the natural history of chemical warfare nerve agent (CWNA) toxicity in animal models that represent the human condition so that the FDA Animal Rule may be used to develop effective medical countermeasures (MCM) against chemicals that cannot be assessed in humans. Currently there are no approved MCM to treat status epilepticus (SE) that is refractory to benzodiazepine therapy when treatment is delayed after CWNA exposure or the long-term functional and neuropathological effects of CWNA exposure. Minipigs, which are similar in anatomy and physiology to humans, are increasingly being used as large animal alternatives to nonhuman primates. The goal is to develop, characterize and qualify the Gottingen minipig as a large animal for MCM development to predict effects in humans. A few studies have been conducted using the minipig to assess lethality and cardiotoxicity of CWNA exposure (e.g. Hulet et al., 2014) and to assess the efficacy of MCM in increasing survival against CWNA (Saxena, 2011, 2015), the potential for the minipig to be used as a large animal model to assess seizure-induced brain pathology after exposure to CWNA and to evaluate MCM has not been assessed. A recent study used the Gottingen minipig as an experimental model to show neuronal loss following multiple blasts including loss of neurons in the hippocampus and neuroinflammatory responses including astrocyte activation and activated microglia (Goodrich et al., 2016). Our specific aim is determine if the Gottingen minipig will be a useful model to evaluate neuroprotective effects of MCM against CWNA exposure. We propose to first establish the LD50 for intramuscular exposure to soman and to then evaluate standard MCM of atropine against a lethal challenge dose of soman in minipigs to include delayed treatment with benzodiazepine. Neuropathological effects of soman exposure in minipigs to include neuronal loss and neuroinflammation will be evaluated to determine if this model may be useful as a large animal model for screening FDA-approved anti-epileptic drugs and novel neuroprotectants against soman toxicity. If validated, this model could then be used in future studies to evaluate MCM against CWNA in support of the FDA Animal Rule.

全面描述化学战神经毒剂（CWNA）的自然史具有重要意义。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Soman-induced toxicity, cholinesterase inhibition and neuropathology in adult male Göttingen minipigs.

DOI：
10.1016/j.toxrep.2021.04.005
发表时间：
2021
期刊：
Toxicology reports
影响因子：
0
作者：
Lumley L;Du F;Marrero-Rosado B;Stone M;Keith ZM;Schultz C;Whitten K;Walker K;Acon-Chen C;Wright L;Shih TM
通讯作者：
Shih TM