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: 7684032
• 负责人: P. A. Ferchmin
• 金额: $ 64.98万
• 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/7684032
• 关键词: PROTECTION; AGAINST; ORGANOPHOSPHATE; NEUROTOXINS; TOBACCO

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 该项目的长期目标是开发一种针对有机磷神经毒素（如梭曼和沙林）的新型解毒剂。人们对恐怖威胁的认识不断增强，促使人们制定了防御神经毒素袭击的策略。最有可能使用的神经毒素是有机磷（OP）神经毒素，以前曾用于对付军事和平民。 OP 会抑制大脑和周围神经中的乙酰胆碱酯酶 (AChE)，导致胆碱能危机，如果不及时治疗，可能致命。现在使用的经典解毒剂可以防止广泛的神经损伤并显着降低死亡率。然而，它们未能靶向由有毒OP引发的神经元凋亡，从而导致长期神经功能损伤。在这里，我们建议测试一种新型神经保护化合物 (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R)。 4R 神经保护是由烟碱抗凋亡机制介导的，该机制在体外和体内模型中均有效。 4R 无毒，具有良好的药理学特性，具有抗凋亡和抗炎特性。由于在解毒剂开发的早期阶段使用战争神经毒素是不切实际的，因此将针对两种毒性较小的类似物对氧磷 (POX) 和二异丙基氟磷酸盐 (DFP) 来测试 4R 的神经保护功效。这里提出的第一个目标是在体外模型中针对 POX 和 DFP 测试 4R。 4R 的体外神经保护活性将单独进行测试，并与经典解毒剂结合使用。用于体外研究的模型是海马切片。毒素造成的损害将通过电生理学和组织学方法确定。第二个目标是利用大鼠模型研究 4R 对体内两种毒素的功效。 4R 与经典解毒剂的几种组合将针对不同剂量的 POX 和 DFP 进行测试。行为、生理和组织学测定将用于确定 4R 的功效。第三个目标是通过与经典解毒剂的各种组合来研究 4R 神经保护的治疗机会窗口。评估有机磷酸酯和 4R 神经保护毒性作用的变量将如目标 2 中所示。 从公共卫生的角度来看，对军事或平民OPs中毒治疗的任何改进都将对人类的痛苦和相关费用产生巨大的价值。 OPs暴露的风险不仅限于战争场景或恐怖袭击，还包括杀虫剂的工业泄漏、意外中毒和长期职业暴露。