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.

甲基吡啶(PAM)型4-PAO能重新激活被烷基膦抑制的AChE，并能穿透血脑屏障，有望有效地重新激活被阻断的脑胆碱酯酶。然而，4-PAO的毒性还没有得到详细的研究。本研究采用心电分析的方法，研究了4-PAO对大鼠心脏收缩活动的影响。4-PAO对房室传导系统的抑制作用强于2-PAM。此外，4-PAO和2-PAM对肌球蛋白固有的K+-EDTA-ATPase催化活性均有抑制作用，提示肟类化合物可能直接与肌球蛋白分子的催化中心相互作用。对临床剂量的4-PAO、2-PAM、4-PAPE、奥比定和DAM均未见明显抑制作用。4-PAO的毒性机制尚需进一步研究。

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