PROTECTION AGAINST ORGANOPHOSPHATE NEUROTOXINS BY TOBACCO CEMBRANOIDS

烟草总皂甙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对抗有机磷神经的解毒剂。 像梭曼和沙林这样的毒素。人们对恐怖主义威胁的认识不断增强，促使 针对神经毒素攻击的保护策略。最有可能使用的神经毒素是 有机磷(OP)神经毒素，以前曾用于军事和平民人口。 OPs抑制大脑和周围神经中的乙酰胆碱酯酶(AChE)，导致胆碱能危象 如果不治疗是致命的。现在使用的经典解毒剂可以预防广泛的神经损伤和 大大降低了死亡率。然而，它们未能针对由有毒OP引发的神经元凋亡 允许长期的神经损伤。在这里，我们建议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)。4R神经保护是由尼古丁介导的 在体外和体内模型中发现了有效的抗凋亡机制。4R无毒，具有良好的 具有抗细胞凋亡和抗炎特性的药理学概况。自从战争神经毒素的使用以来 在解毒剂开发的早期阶段是不切实际的4R的神经保护效果将得到测试 对抗两种毒性较小的类似物，对氧磷(POX)和二异丙基氟磷酸盐(DFP)。第一个目标 这里提出的是在体外模型中测试4R抗POX和DFP。银杏叶提取物的体外神经保护作用 4R将单独测试，并与经典解毒剂联合测试。将用于体外实验的模型 研究对象是海马片。毒素造成的损害将通过以下方式确定 电生理和组织学方法。第二个目标将解决4R对这两种疾病的疗效 用大鼠模型研究体内毒素。将对几种与经典解毒剂组合的4R进行测试 不同剂量的痘和DFP。行为学、生理学和组织学测定将用于 确定4R的疗效。第三个目标是4R神经保护的治疗机会之窗 将在与经典解毒剂的各种组合中进行研究。评估有毒物质的变量 有机磷和4R神经保护的效果将与目标2相同。 从公共卫生的角度来看，军民有机磷农药中毒治疗方面的任何改进 人口将对人类的痛苦和所涉及的代价具有巨大的价值。OPS暴露的风险不是 仅限于战争场景或恐怖袭击，但包括工业杀虫剂泄漏，意外 中毒和长期职业接触。

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.