PROTECTION AGAINST ORGANOPHOSPHATE NEUROTOXINS BY TOBACCO CEMBRANOIDS

烟草西松素对有机磷酸盐神经毒素的保护

• 批准号: 7696144
• 负责人: P. A. Ferchmin
• 金额: $ 66.99万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696144
• 关键词: Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Address; Adult; Agricultural Workers; Agriculture; Animals; Anti-Inflammatory Agents; Antidotes; Apoptotic; Asses; Atropine; Awareness; Bathing; Behavior; Behavioral; Benzodiazepines; Brain; Brain Injuries; Caspase; Cessation of life; Cholinergic Agents; Chronic; Competence; Development; Dose; Gait; General Population; Glycol; Hippocampus (Brain); Hour; Human; Impairment; In Situ Nick-End Labeling; In Vitro; Infarction; Injury; Insecticides; Isoflurophate; Literature; Measures; Mediating; Medical; Methods; Midazolam; Middle Cerebral Artery Occlusion; Military Personnel; Modeling; Nerve; Neurologic; Neurons; Neuroprotective Agents; Neurotoxins; Occupational Exposure; Organophosphates; Outcome Measure; Oximes; Paraoxon; Peripheral Nerves; Pharmaceutical Preparations; Phase; Physiological; Physiological Processes; Poisoning; Population; Posture; Property; Public Health; Range; Rattus; Recovery; Reporting; Risk; Sarin; Seizures; Slice; Soman; Staging; Stimulus; Testing; Therapeutic; Tobacco; Toxic effect; Toxin; Vertebral column; War; analog; cholinergic; cost; density; excitotoxicity; in vitro Model; in vivo; in vivo Model; indexing; male; mortality; nerve agent; nerve injury; neuron apoptosis; neuroprotection; neurotoxic; novel; organophosphate poisoning; prevent; research study; response; toxic organophosphate insecticide exposure

PROTECTION AGAINST ORGANOPHOSPHATE NEUROTOXINS BY TOBACCO CEMBRANOIDS The long term objective of this project is to develop a novel antidote against the organophosphate nerve toxins like soman and sarin. The increased awareness of terrorist threats prompted the development of strategies for protection against nerve toxin attacks. The most likely nerve toxins to be used are the organophosphate (OP) neurotoxins that have been used before against military and civilian populations. OPs inhibit the acetylcholinesterase (AChE) in brain and peripheral nerves, causing a cholinergic crisis that is fatal if untreated. The classic antidotes now in use protect against a wide spectrum of neural injury and dramatically decrease mortality. They fail, however, to target neuronal apoptosis initiated by the toxic OP allowing for long term neurological impairment. Here we propose to test a novel neuroprotective compound the (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R). 4R neuroprotection is mediated by a nicotinic antiapoptotic mechanism found effective in in vitro and in vivo models. 4R is not toxic and has a favorable pharmacological profile with antiapoptotic and antiinflammatory properties. Since the use of war neurotoxins is impractical in the early stages of antidotes development the neuroprotective efficacy of 4R will be tested against two less toxic analogues, paraoxon (POX) and diisopropylfluorophosphate (DFP). The first objective proposed here is to test 4R in an in vitro model against POX and DFP. The in vitro neuroprotective activity of 4R will be tested alone and in combination with the classical antidotes. The model to be used for the in vitro studies is the hippocampal slice. The damage inflicted by the toxins will be determined by electrophysiological and histological methods. The second aim will address the efficacy of 4R against both toxins in vivo using a rat model. 4R in several combinations with classical antidotes will be tested against various doses of POX and DFP. Behavioral, physiological, and histological determinations will be used to determine the efficacy of 4R. In the third aim the window of therapeutical opportunity for 4R neuroprotection will be investigated in various combinations with the classical antidotes. The variables to asses the toxic effect of the organophosphates and of 4R neuroprotection will be as in aim 2. From the public health perspective any improvement in the treatment of OPs poisoning of military or civilian population would be of great value in human suffering and costs involved. The risk of OPs exposure is not restricted to war scenario or terrorist attacks but includes industrial leaks of insecticides, accidental poisonings and chronic occupational exposure.

烟草类胚状体对有机磷神经毒素的保护作用 该项目的长期目标是开发一种新的抗有机磷神经毒剂 梭曼和沙林之类的毒素对恐怖主义威胁的认识提高， 防止神经毒素攻击的策略。最有可能使用的神经毒素是 有机磷酸盐（OP）神经毒素，以前曾用于军事和平民人口。 OP抑制脑和外周神经中的乙酰胆碱酯酶（AChE），引起胆碱能危象， 如果不治疗是致命的现在使用的经典解毒剂可以防止广泛的神经损伤， 大大降低死亡率。然而，它们未能针对有毒OP引发的神经元凋亡 导致长期神经损伤在这里，我们打算测试一种新的神经保护化合物， （1S，2E，4R，6R，7E，11E）-cembra-2，7，11-triene-4，6-diol（4R）。4 R神经保护作用是由烟碱 在体外和体内模型中发现有效的抗凋亡机制。4 R无毒，具有良好的生物相容性。 具有抗凋亡和抗肿瘤特性的药理学特征。自从战争神经毒素的使用 在解毒剂开发的早期阶段是不切实际的，将测试4 R的神经保护功效。 对抗两种毒性较小的类似物，对氧磷（POX）和二异丙基氟磷酸（DFP）。第一个目标 本文提出的是在体外模型中测试4 R对POX和DFP的作用。体外神经保护活性 4 R将单独测试和与经典解毒剂组合测试。用于体外试验的模型 研究的是海马切片。毒素造成的伤害将由 电生理学和组织学方法。第二个目标将解决4 R对这两种疾病的疗效。 毒素在体内使用大鼠模型。将测试4 R与经典解毒剂的几种组合， 不同剂量的POX和DFP行为、生理和组织学测定将用于 4 R的功效。在第三个目标中，4 R神经保护的治疗机会窗口 将与经典解毒剂进行各种组合研究。评估毒性的变量 有机磷酸酯和4 R神经保护的效果将如目的2中所述。 从公共卫生的角度来看，对军事或平民的有机磷农药中毒治疗的任何改进， 在人类痛苦和所涉费用方面，人口将具有巨大价值。OP暴露的风险不是 仅限于战争情景或恐怖袭击，但包括杀虫剂的工业泄漏、意外泄漏、 中毒和慢性职业接触。