Acute Toxic Injuries of Rat\u2019s Visceral Tissues Induced by Different Oximes

Vesna Jaćević,Kamil Kuča,Eugenie Nepovimova

doi:10.1038/s41598-019-52768-4

Vesna Jaćević, Kamil Kuča + Show 1 more

Open Access

https://doi.org/10.1038/s41598-019-52768-4

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Abstract

Certain AChE reactivators, asoxime, obidoxime, K027, K048, and K075, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the different organs. As a continuation of previously published data, in this study, Wistar rats have sacrificed 24 hrs and 7 days after single im application of 0.1LD50, 0.5LD50 and 1.0LD50 of each reactivator, and examinated tissue samples were obtained for pathohistological and semiquantitative analysis. A severity of tissue alteration, expressed as different tissue damage scores were evaluated. Morphological structure of examinated tissues treated with of 0.1LD50 of all reactivators was comparable with the control group of rats. Moderate injuries were seen in visceral tissues treated with 0.5LD50 of asoxime, obidoxime and K027. Acute damages were enlarged after treatment with 0.5LD50 and 1.0LD50 of all reactivators during the next 7 days. The most prominent changes were seen in rats treated with 1.0LD50 of K048 and K075 (P < 0.001 vs. control and asoxime-treated group). All reactivators given by a single, high, unitary dose regimen, have an adverse effect not only on the main visceral tissue, but on the whole rat as well, but the exact mechanism of cellular injury remains to be confirmed in further investigation.

Highlights

Organophosphorus compounds are broadly used as pesticides in agriculture or as chemical warfare agents in the military attacks
That is why many institutions involved in this research area try to predict and synthesize the structures of an ideal broad-spectrum AChE reactivator that can reactivate the enzyme inhibited by all types of nerve agents[13,14,15,16,17]
Since all the toxicological data were provided in the earlier studies[25,26], in this third study, we focused our attention on an investigation of morphological lesions of visceral tissue’s produced by increasing doses of selected www.nature.com/scientificreports

Summary

Introduction

Organophosphorus compounds are broadly used as pesticides in agriculture or as chemical warfare agents in the military attacks. Among the most well-known representatives of nerve agents are sarin (GB; O-isopropylmethylfluorophosphate), soman (GD, O-pinacolylmethylfluorophosphate), tabun (GA, O-thyldimethylamidocyanophosphate) and VX (O-ethyl-S- (2-diisopropylaminoethyl) methylthiophosphonate) (Fig. 1). Their toxic effect is based on the inhibition of enzyme acetylcholinesterase (AChE; EC 3.1.1.7) through its phosphorylation. Among the most well-known representatives of this family are pralidoxime (2-PAM, 2-hydroxyiminomethyl-1-methylpyridinium chloride), obidoxime (Toxogonin, 1,3- bis(4-hydroxyiminomethylpyridinium)-2-oxo-propane dichloride) or asoxime (1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride) (Fig. 2). Their reactivating effect lies in cleavage of the binding resulting from inhibition between the enzyme and the nerve agents[11,12]. That is why many institutions involved in this research area try to predict and synthesize the structures of an ideal broad-spectrum AChE reactivator that can reactivate the enzyme inhibited by all types of nerve agents[13,14,15,16,17]

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