Abstract
The capability of the tertiary oximes, monoisonitrosoacetone (MINA) and diacetylmonoxime (DAM), to reactivate acetylcholinesterase (AChE) inhibited by sarin (GB) in the blood, brain, and peripheral tissues of guinea pigs was compared with that of the quaternary oximes 2-PAM, HLö7, and MMB-4. Animals were injected subcutaneously (s.c.) with 1.0 × LD50 of GB and treated intramuscularly (i.m.) 5 min later with one of these oximes. Sixty minutes after GB exposure, tissues were collected for AChE analysis. At low doses, MINA and DAM produced significant increases in AChE activity in all brain areas examined, but no significant AChE reactivation in peripheral tissues or blood. At higher doses, MINA and DAM increased AChE activity in the brain, peripheral tissues, and blood. In contrast, the quaternary oximes produced significant reactivation in peripheral tissues and blood AChE, but no significant reactivation of brain AChE. In another study, animals were pretreated i.m. with pyridostigmine 30 min prior to s.c. challenge with 2.0 × LD50 of GB and treated i.m. 1 min later with atropine sulfate (2.0 mg/kg), plus a varied dose of oximes. MINA and DAM prevented or terminated GB-induced seizure activity and protected against GB lethality in a dose-dependent fashion. In contrast, none of the quaternary oximes prevented or stopped GB-induced seizures. Thus, tertiary oximes reactivated AChE in the brain, improved survival, and terminated seizures following GB intoxication.
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Acknowledgements
The authors wish to recognize the excellent technical assistance of Farah Bader, Cindy Acon-Chen, John LaMont, Megan Lyman, Mychael Scott, Kerry Van Shura, and Alexis Yahyavi. This research was supported by the Defense Threat Reduction Agency–Joint Science and Technology Office, Medical S&T Division.
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Proceedings of the XIII International Symposium on Cholinergic Mechanisms
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. In conducting the research described in this report, the investigators adhered to the Guide for the Care and Use of Laboratory Animals by the Institute of Laboratory Animal Resources, National Research Council, in accordance with the stipulation mandated for an Association for Assessment and Accreditation of Laboratory Animal Care International-accredited facility.
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Shih, TM., Skovira, J.W., O’Donnell, J.C. et al. Treatment with Tertiary Oximes Prevents Seizures and Improves Survival Following Sarin Intoxication. J Mol Neurosci 40, 63–69 (2010). https://doi.org/10.1007/s12031-009-9259-7
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DOI: https://doi.org/10.1007/s12031-009-9259-7