The Tertiary Oxime Monoisonitrosoacetone Penetrates the Brain, Reactivates Inhibited Acetylcholinesterase, and Saves Lives following Lethal Sarin Intoxication in Guinea Pigs
Technical Report,01 Oct 2009,30 Sep 2012
ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD ABERDEEN PROVING GROUND United States
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The brain is a critical target for the toxic action of organophosphorus OP inhibitors of acetylcholinesterase AChE such as the nerve agent sarin. However, current oxime antidotes such as 2-PAM only reactivate OP-inhibited AChE in peripheral tissues. Monoisonitrosoacetone MINA is a tertiary oxime that can enter the central nervous system CNS. The purpose of this study was to investigate whether MINA would be beneficial as a supplemental oxime treatment in preventing lethality and reducing morbidity following lethal sarin intoxication. Guinea pigs were exposed to sarin and treated with atropine sulfate and 2-PAM at one min. Additional 2-PAM or MINA was administered at 1, 3, 5, 15, or 30 min after sarin exposure. Control animals received no additional treatment after one min. Survival and morbidity were assessed at 2 and 24 hours. AChE activity in brain and peripheral tissues was evaluated one hour after MINA or 2-PAM treatment. Microdialysis technique was used to determine partitioning of MINA into the brain. A liquid chromatograph-tandem mass spectrometric method was developed for the analysis of MINA in low volume microdialysis samples. MINA-treated animals exhibited significantly higher survival and lower morbidity compared to 2-PAM-treated animals. 2-PAM was significantly more effective in reactivating AChE in peripheral tissues, but only MINA reactivated inhibited AChE in the CNS. MINA was found in guinea pig brain microdialysate samples beginning at tilde10 minutes after administration. The data strongly suggest that a centrally penetrating oxime could provide significant benefit as an adjunct to atropine and 2-PAM treatment for OP intoxication.
- Chemical, Biological and Radiological Warfare