A comparison of tabun-inhibited rat brain acetylcholinesterase reactivation by three oximes (HI-6, obidoxime, and K048) in vivo detected by biochemical and histochemical techniques

Tabun belongs to the most toxic nerve agents. Its mechanism of action is based on acetylcholinesterase (AChE) inhibition at the peripheral and central nervous systems. Therapeutic countermeasures comprise administration of atropine with cholinesterase reactivators able to reactivate the inhibited en...

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Bibliographic Details
Published in:	Journal of enzyme inhibition and medicinal chemistry Vol. 25; no. 6; p. 790
Main Authors:	Bajgar, Jiri, Hajek, Petr, Zdarova, Jana Karasova, Kassa, Jiri, Paseka, Antonin, Slizova, Dasa, Krs, Otakar, Kuca, Kamil, Jun, Daniel, Fusek, Josef, Capek, Lukas
Format:	Journal Article
Language:	English
Published:	England 01-12-2010
Subjects:	Acetylcholinesterase - metabolism Animals Atropine Brain - drug effects Brain - enzymology Brain - pathology Chemical Warfare Agents - toxicity Cholinesterase Inhibitors - administration & dosage Cholinesterase Inhibitors - toxicity Cholinesterase Reactivators - administration & dosage Cholinesterase Reactivators - pharmacology Cholinesterase Reactivators - therapeutic use Female Frontal Lobe - drug effects Frontal Lobe - enzymology Frontal Lobe - pathology GPI-Linked Proteins - metabolism Lethal Dose 50 Obidoxime Chloride - administration & dosage Obidoxime Chloride - pharmacology Obidoxime Chloride - therapeutic use Organ Specificity Organophosphates - administration & dosage Organophosphates - antagonists & inhibitors Organophosphates - toxicity Oximes - administration & dosage Oximes - pharmacology Oximes - therapeutic use Pyridinium Compounds - administration & dosage Pyridinium Compounds - pharmacology Pyridinium Compounds - therapeutic use Rats Rats, Wistar Reticular Formation - drug effects Reticular Formation - enzymology Reticular Formation - pathology
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Summary:	Tabun belongs to the most toxic nerve agents. Its mechanism of action is based on acetylcholinesterase (AChE) inhibition at the peripheral and central nervous systems. Therapeutic countermeasures comprise administration of atropine with cholinesterase reactivators able to reactivate the inhibited enzyme. Reactivation of AChE is determined mostly biochemically without specification of different brain structures. Histochemical determination allows a fine search for different structures but is performed mostly without quantitative evaluation. In rats intoxicated with tabun and treated with a combination of atropine and HI-6, obidoxime, or new oxime K048, AChE activities in different brain structures were determined using biochemical and quantitative histochemical methods. Inhibition of AChE following untreated tabun intoxication was different in the various brain structures, having the highest degree in the frontal cortex and reticular formation and lowest in the basal ganglia and substantia nigra. Treatment resulted in an increase of AChE activity detected by both methods. The highest increase was observed in the frontal cortex. This reactivation was increased in the order HI-6 < K048 < obidoxime; however, this order was not uniform for all brain parts studied. A correlation between AChE activity detected by histochemical and biochemical methods was demonstrated. The results suggest that for the mechanism of action of the nerve agent tabun, reactivation in various parts of the brain is not of the same physiological importance. AChE activity in the pontomedullar area and frontal cortex seems to be the most important for the therapeutic effect of the reactivators. HI-6 was not a good reactivator for the treatment of tabun intoxication.
ISSN:	1475-6374
DOI:	10.3109/14756360903433373