Central Acetylcholinesterase Reactivation by Oximes Improves Survival and Terminates Seizures Following Nerve Agent Intoxication

The current treatment regimen for organophosphorus nerve agent intoxication depends on the ability of oximes to rapidly reactivate nerve agent-inhibited acetylcholinesterase (AChE) activity. We have studied the capability of the tertiary oximes monoisonitrosoacetone (MINA) and diacetylmonoxime (DAM), in comparison with the quaternary oximes 2-PAM, HLö7 and MMB-4, to reactivate AChE inhibited by sarin (GB) in blood, brain regions (cortex, hippocampus, striatum, midbrain, cerebellum, brainstem, and spinal cord) and peripheral tissues (heart, diaphragm and skeletal muscle) of guinea pigs. Animals were injected subcutaneously (sc) with 1.0 x LD50 of GB and treated intramuscularly (im) five min later with one of the oximes (MMB-4 and HLö7 at 58 μmol/kg, im and 2-PAM, MINA and DAM at 145 μmol/kg, im). Sixty min after nerve agent, blood and tissues were collected and prepared for AChE analysis. All animals survived the 60 min after exposure. AChE reactivation in peripheral tissues and blood was insignificant and in brain regions was significant after treatment with MINA and DAM, whereas AChE reactivation from the quaternary oximes was significant in blood and peripheral tissues, but insignificant in the brain. In another study, animals were pretreated im with pyridostigmine bromide 30 min prior to sc challenge with 2.0 x LD50 of GB, and treated im one min later with a combination of atropine sulfate (2.0 mg/kg) and a varied dose of MINA or DAM. With MINA doses of 20, 26, 35, 46 and 60 mg/kg, there were 0, 9, 17, 60, and 75%, respectively, of animals never exhibited EEG seizure activity with 43, 64, 75, 90, and 100%, respectively, survival at 24 hr. With DAM in the dose range from 41 to 231 mg/kg, similar results were obtained. Quaternary oximes did not prevent or stop seizures. These data show that the tertiary oximes reactivated AChE in the brain, improved survival and eliminated or terminated seizures following GB intoxication.