REVERSING THE EFFECTS OF ORGANOPHOSPHORUS PESTICIDES

乙酰胆碱酯酶抑制剂用作杀虫剂、杀线虫、 杀螨剂、杀菌剂等对环境有相当大的影响 对农业工人和其他人的健康造成危害。它是 因此，有必要充分了解 这些物质可以阻断突触传递，从而 对于那些意外患病的人，可以设计出有效的治疗方法 中毒了。在我们建议的研究中， 有机磷中具有代表性的抗AChE农药 和氨基甲酸酯家族将在哺乳动物中进行研究 神经肌肉接头。初步研究表明， 乙酰胆碱酯酶抑制剂可阻断神经肌肉传递 由于突触后膜的去极化 只有当神经受到刺激时才会发生。肌肉 对火车上的第一次神经刺激反应正常，但 随后的刺激效果很小，甚至没有效果。后 刺激训练结束，肌肉迅速恢复正常。 我们的假设是，在AChE阻断后，终板电位 是如此之大，如此之长，以至于去极化的积聚 以及依赖于频率的传输块。后脑筋 活性停止，膜迅速恢复正常，由于 正常，因为过量的ACh从 端板。在初步研究中，我们发现这种传播 可以在该传输块之后通过使用 减少幅度和时间的药理学程序 终板电势的常数。这些程序包括 钙水平的降低进而减少突触前 释放ACh。或者，突触后的阻断 某些药物分子的受体也可以逆转这种 乙酰胆碱酯酶抑制剂引起的神经肌肉阻滞。我们提出了一个 这些治疗程序的详细分析和 调查将提供关于其确切情况的有用信息 行动模式。这些研究将测量突触前和突触前 突触后事件，还将使用一种特殊的仪器， 肌肉收缩和复合动作电位可以 同时测量。

Acetylcholinesterase inhibitors used as insecticides, nematocides, acaricides, fungicides, etc., present a considerable environmental hazard to the health of agricultural workers and others. It is therefore necessary to fully understand the mode of action of these substances in blocking synaptic transmission so that effective treatments can be devised for those who are accidently poisoned. In our proposed studies the mode of action of representative anti-AChE pesticides from the organophosphate and carbamate families will be studied at the mammalian neuromuscular junction. Preliminary studies have shown that block of neuromuscular transmission by AChE inhibitors can be due to a depolarization of the postsynaptic membrane which occurs only while the nerve is being stimulated. The muscle responds normally to the first nerve stimulation in a train but subsequent stimulation has little or no effect. After the stimulation train is ended, the muscle rapidly returns to normal. Our hypothesis is that after block of AChE, the endplate potential is so large and so long that there is a build up of depolarization and a frequency dependent block of transmission. After the nerve activity ceases, the membrane quickly returns to normal due to normal due to the rapid diffusion of excess ACh from the endplate. In preliminary studies we have found that transmission may be restored after this transmission block, by using pharmacological procedures which reduce the amplitude and time constant of the endplate potential. These procedures include the reduction of calcium levels which in turn reduces the presynaptic release of ACh. Alternatively, the postsynaptic blockade of receptors by certain drug molecules also reverses the neuromuscular block induced by AChE inhibitors. We propose a detailed analysis of these therapeutic procedures and investigations which will provide useful information on their exact modes of action. The studies will measure both presynaptic and postsynaptic events and will also use a special apparatus where muscle contraction and compound action potential can be measured simultaneously.