Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
Toxicol Mech Methods. 2010 Mar;20(3):143-52. doi: 10.3109/15376511003657439.
Organophosphorus nerve agents irreversibly inhibit acetylcholinesterase (AChE) in the peripheral and central nervous systems, causing an increase in the concentration of acetylcholine (ACh) in the synapse or neuromuscular junction and subsequent adverse effects. In this study, in vivo microdialysis was utilized to collect samples from the striatum for monitoring changes in extracellular ACh levels along with cortical electroencephalographic (EEG) recordings for identifying seizure activity after acute subcutaneous (s.c.) exposure to 1.0 x LD(50) of the nerve agents sarin, soman, or one of two V-type agents (VX, or a Russian V-agent, designated VR) in unanesthetized freely moving guinea pigs. Based on EEG recordings, these animals were subsequently divided into groups that developed seizures (S) and those that did not develop seizures (NS). Maximum ACh levels in the striatum were observed at 60-70 min for sarin and soman S groups and 105 min for VX and VR S groups. In all NS groups the greatest increase in extracellular ACh occurred within 30 min after exposure, although in the sarin NS group a few sporadic increases of ACh from control occurred. Animals that developed seizures, regardless of the nerve agent, had significantly higher extracellular striatal ACh levels compared to the controls or those animals that did not develop seizures, yet both S and NS groups displayed similar levels of blood AChE inhibition. Regardless of the agent, all animals in the non-seizure groups survived 24 h, while lethality (25-42%) was observed only in animals that experienced seizure activity.
有机磷神经毒剂会不可逆地抑制周围神经系统和中枢神经系统中的乙酰胆碱酯酶（AChE），导致突触或神经肌肉接头中乙酰胆碱（ACh）浓度增加，从而产生不良影响。在这项研究中，我们利用体内微透析技术从纹状体采集样本，以监测急性皮下（s.c.）暴露于沙林、梭曼或两种 V 型毒剂（VX 或一种俄罗斯 V 型毒剂，称为 VR）1.0 x LD(50)后细胞外 ACh 水平的变化，并同时进行皮质脑电图（EEG）记录以识别癫痫发作活动。根据 EEG 记录，这些动物随后被分为发生癫痫发作（S）和未发生癫痫发作（NS）的两组。沙林和梭曼 S 组的纹状体中 ACh 水平最高出现在 60-70 分钟，而 VX 和 VR S 组则出现在 105 分钟。在所有 NS 组中，暴露后 30 分钟内细胞外 ACh 水平的增加最大，尽管沙林 NS 组中偶尔会出现对照水平的 ACh 增加。无论神经毒剂如何，发生癫痫发作的动物的纹状体细胞外 ACh 水平明显高于对照动物或未发生癫痫发作的动物，但 S 和 NS 组均显示出相似的血液 AChE 抑制水平。无论毒剂如何，非癫痫发作组的所有动物均存活 24 小时，而仅在经历癫痫发作活动的动物中观察到致死率（25-42%）。
