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Effects of 4-pyridine aldoxime on nerve agent-inhibited acetylcholinesterase activity in guinea pigs

  • Organ Toxicity and Mechanisms
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Abstract

Methoxime (MMB-4) is a leading candidate oxime acetylcholinesterase (AChE) reactivator to replace pralidoxime (2-PAM) for therapeutic treatment of nerve agent intoxication. 4-Pyridine aldoxime (4-PA) is a synthetic starting material, a breakdown product, and a probable metabolite of MMB-4. There is a possibility that 4-PA may adversely interact with the nerve agent, thereby affecting nerve agent toxicity and biological AChE activity. This study evaluated the effects of 4-PA on sarin (GB)-, cyclosarin (GF)-, and VX-induced toxicity and AChE activity in blood, brain, and peripheral tissues of guinea pigs. Animals were pretreated with atropine methyl nitrate (1.0 mg/kg, im) 15 min prior to subcutaneous administration with 1.0× LD50 of GB, GF, or VX and then treated 15 min after the administration of nerve agents with 4-PA (3.5, 7.0, or 14.0 mg/kg, im). The dose–response effects of 4-PA alone were also examined. Toxic signs and lethality were monitored, blood and tissues were collected, and AChE activities were determined at 60 min after nerve agent administration. Under the condition of this study, all animals exposed to nerve agents exhibited some degree of toxic signs such as salivation, lacrimation, rhinorrhea, and convulsions. 4-PA at the three doses tested neither induced toxic signs nor altered the toxicity of GB, GF, or VX at the 1.0× LD50 exposure dose. Additionally, it did not modify the AChE activity in blood, brain, and peripheral tissues by itself or affect the AChE activity inhibited by a 1.0× LD50 dose of these three nerve agents in guinea pigs.

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

AMN:

Atropine methyl nitrate

ChE:

Cholinesterase

BCA:

Bicinchoninic acid

DTNB:

5,5′-Dithiobis-2-nitrobenzoic acid

GB:

Sarin

GF:

Cyclosarin

im:

Intramuscular

LD50 :

Median lethal dose

MMB-4:

Methoxime

OP:

Organophosphorus compound

2-PAM:

Pralidoxime; pyridine-2-aldoxime methylchloride

4-PA:

4-Pyridine aldoxime

PB:

Pyridostigmine bromide

RBC:

Red blood cell

sc:

Subcutaneous

WB:

Whole blood

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Acknowledgments

Excellent technical team work of John Guarisco, John O’Donnell, Anna Smelley, Kerry van Shura, Cindy Acon-Chen, Shelby Brooks, Jessica Chandler, Teresa Ferrara, Jeff Koenig, Megan Lyman, and Kristin Tarzia is acknowledged. This research was supported by the Medical Identification and Treatment Systems Joint Product Management Office, U.S. Army Medical Research and Materiel Command.

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Authors and Affiliations

  1. Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P, 3100 Ricketts Point Road, Aberdeen Proving Ground, Aberdeen, MD, 21010-5400, USA

    Tsung-Ming Shih, Jacob W. Skovira & John H. McDonough

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  1. Tsung-Ming Shih
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  2. Jacob W. Skovira
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  3. John H. McDonough
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Correspondence to Tsung-Ming Shih.

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Research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and experiments involving animals and adhered to principles stated in the Guide for the Care and Use of Laboratory Animals, by the Institute of Laboratory Animal Resources, National Research Council. The research environment and protocols for animal experimentation were approved by the Institutional Animal Care and Use Committee (IACUC) of the US Army Medical Research Institute of Chemical Defense. The facility where this research was conducted is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.

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Shih, TM., Skovira, J.W. & McDonough, J.H. Effects of 4-pyridine aldoxime on nerve agent-inhibited acetylcholinesterase activity in guinea pigs. Arch Toxicol 83, 1083–1089 (2009). https://doi.org/10.1007/s00204-009-0465-4

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  • DOI: https://doi.org/10.1007/s00204-009-0465-4

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