Research and Analytical Toxicology Divisions, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
Toxicol Mech Methods. 2011 Jan;21(1):53-62. doi: 10.3109/15376516.2010.529190. Epub 2010 Nov 30.
This study examined whether pro-2-PAM, a pro-drug dihydropyridine derivative of the oxime 2-pralidoxime (2-PAM) that can penetrate the brain, could prevent or reverse the central toxic effects of three nerve agents; sarin, cyclosarin, and VX. The first experiment tested whether pro-2-PAM could reactivate guinea pig cholinesterase (ChE) in vivo in central and peripheral tissues inhibited by these nerve agents. Pro-2-PAM produced a dose-dependent reactivation of sarin- or VX-inhibited ChE in both peripheral and brain tissues, but with substantially greater reactivation in peripheral tissues compared to brain. Pro-2-PAM produced 9-25% reactivation of cyclosarin-inhibited ChE in blood, heart, and spinal cord, but no reactivation in brain or muscle tissues. In a second experiment, the ability of pro-2-PAM to block or terminate nerve agent-induced electroencephalographic seizure activity was evaluated. Pro-2-PAM was able to block sarin- or VX-induced seizures (16-33%) over a dose range of 24-32 mg/kg, but was ineffective against cyclosarin-induced seizures. Animals that were protected from seizures showed significantly less weight loss and greater behavioral function 24 h after exposure than those animals that were not protected. Additionally, brains were free from neuropathology when pro-2-PAM prevented seizures. In summary, pro-2-PAM provided modest reactivation of sarin- and VX-inhibited ChE in the brain and periphery, which was reflected by a limited ability to block or terminate seizures elicited by these agents. Pro-2-PAM was able to reactivate blood, heart, and spinal cord ChE inhibited by cyclosarin, but was not effective against cyclosarin-induced seizures.
本研究旨在探讨前体-2-PAM（肟 2-吡啶甲羟肟酸（2-PAM）的前药二氢吡啶衍生物，可穿透大脑）是否能够预防或逆转三种神经毒剂：沙林、梭曼和 VX 对中枢的毒性作用。第一项实验检测了前体-2-PAM 是否能够使这些神经毒剂抑制的豚鼠中枢和外周组织中的胆碱酯酶（ChE）在体内重新激活。结果显示，前体-2-PAM 能使沙林或 VX 抑制的外周和脑组织中的 ChE 产生剂量依赖性的重新激活，而在外周组织中的重新激活程度显著高于脑。前体-2-PAM 能使环沙林抑制的血、心和脊髓中的 ChE 产生 9-25%的重新激活，但在脑中或肌肉组织中无重新激活。在第二项实验中，评估了前体-2-PAM 阻断或终止神经毒剂引起的脑电图癫痫发作活动的能力。前体-2-PAM 能在 24-32mg/kg 的剂量范围内阻断沙林或 VX 引起的癫痫发作（16-33%），但对梭曼引起的癫痫发作无效。与未受保护的动物相比，免受癫痫发作影响的动物在接触后 24 小时体重减轻和行为功能明显减少，并且大脑免受神经病理学影响。总之，前体-2-PAM 能在脑和外周组织中适度地重新激活沙林和 VX 抑制的 ChE，这反映出其阻断或终止这些神经毒剂引发的癫痫发作的能力有限。前体-2-PAM 能重新激活被环沙林抑制的血、心和脊髓中的 ChE，但对环沙林引起的癫痫发作无效。
