Investigation of the toxic mechanism of oximes which are used in the treatment of poisoning by nerve agents

肟用于治疗神经毒剂中毒的毒性机制研究

• 批准号: 23592690
• 负责人: SAKURADA Koichi
• 金额: $ 2.16万
• 依托单位: National Research Institute of Police Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23592690/
• 关键词: 4-PAO; 2-PAM; cardiac effect; ECG; actomyosin; ATPase; 神経ガス; オキシム; パム

The pyridinium aldoxime methiodide (PAM)-type oxime 4-PAO, which can reactivate AChE inhibited by alkylphosphonate and penetrate the blood-brain barrier, is expected to be effective for reactivating blocked cholinesterase in the brain. However, the toxicity of 4-PAO has not yet been investigated in detail. The present study investigated the effects of 4-PAO on the contractile activity of the rat heart using electrocardiography analysis. 4-PAO was suggested to inhibit the atrioventricular conduction system more strongly than 2-PAM. In addition, not only 4-PAO but also 2-PAM inhibited the inherent K+-EDTA-ATPase catalytic activity of myosin, indicating that oximes might interact directly with the catalytic center of the myosin molecule. No significant inhibition was observed for less than 4uM 4-PAO, 2-PAM, 4-PAPE, obidoxime and DAM, which correspond to the clinical dose of 2-PAM. Further studies are required to clarify the mechanism of 4-PAO toxicity.

吡啶醛氨基甲基碘（PAM） - 型氧蛋白4-PAO，可以重新激活烷基膦酸酯抑制的ACHE并穿透血脑屏障，可有效地在大脑中重新激活阻塞的胆碱酯酶。但是，尚未详细研究4-PAO的毒性。本研究使用心电图分析研究了4-PAO对大鼠心脏收缩活性的影响。建议4-PAO比2-PAM更强烈地抑制心室传导系统。此外，不仅4-PAO而且2-PAM还抑制了肌球蛋白的固有的K+-EDTA-ATPase催化活性，这表明氧气可能与肌球蛋白分子的催化中心直接相互作用。对于小于4-PAO，2-PAM，4-PAPE，OBIDOXIME和DAM的4M-PAO，与2-PAM的临床剂量相对应的4-PA，2-PAM，4-PAPE，4-PAPE，OBIDOXIME和DAM未观察到明显的抑制作用。需要进一步的研究来阐明4-PAO毒性的机制。

项目成果

Development of BBB-penetrative antidotes for reactivation of inhibited AChE in nerve agent poisoning

开发用于神经毒剂中毒中受抑制的 AChE 重新激活的 BBB 渗透解毒剂

• 发表时间: 2012
• 作者: Moriya T.;Sakurai A.;Kinoshita K. and Tanjoh K.;Hikoto Ohta and Koichi Sakurada
• 通讯作者: Hikoto Ohta and Koichi Sakurada