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: 7541195
• 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/7541195
• 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）： 该项目的长期目的是开发一种针对索曼和沙林等有机磷酸神经毒素的新型解毒剂。对恐怖威胁的认识日益增加，促使制定了保护神经毒素攻击的战略。使用最有可能使用的神经毒素是以前用于针对军事和平民的有机磷酸盐（OP）神经毒素。 OPS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，如果未治疗，这是致命的。现在使用的经典解毒剂可以预防广泛的神经损伤，并大大降低了死亡率。但是，他们无法靶向由有毒OP引发的神经凋亡，从而允许长期神经系统损害。在这里，我们建议测试一种新型的神经保护化合物（1S，2E，4R，6R，7E，11E）-CEMBRA-CEMBRA-2,7,11-TRIEENE-4,4,6-二醇（4R）。 4R神经保护是通过发现在体外和体内模型中有效的烟碱抗凋亡机制介导的。 4R没有毒性，具有抗凋亡和抗炎特性的有利的药理学特征。由于在解毒剂发育的早期阶段使用战争神经毒素是不切实际的，因此，将针对两个毒性较低的毒性类似物（Pox）和二异丙丙基磷酸磷酸（DFP）测试4R的神经保护功效。这里提出的第一个目标是在针对POX和DFP的体外模型中测试4R。 4R的体外神经保护活性将单独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。毒素造成的损害将由电生理和组织学方法确定。第二个目的将使用大鼠模型解决4R对两个毒素在体内的疗效。与经典解毒剂的多种组合中的4R将针对各种剂量的POX和DFP进行测试。行为，生理和组织学决定将用于确定4R的疗效。在第三个目的中，将研究与经典解毒剂的各种结合进行4R神经保护机会的窗口。在AIM 2中，有机磷酸盐和4R神经保护作用的变量和4R神经保护作用的变量将与AIM 2一样。 从公共卫生的角度来看，对军事或平民人口中毒的治疗的任何改善在人类苦难和所涉及的成本中都具有很大的价值。 OP接触的风险不仅限于战争的情况或恐怖袭击，而包括杀虫剂，意外中毒和长期职业暴露的工业泄漏。