J Appl Biomed 12:111-117, 2014 | DOI: 10.1016/j.jab.2013.04.002

Comparison of the neuroprotective effects of a novel bispyridinium oxime KR-22934 with the oxime K203 and obidoxime in tabun-poisoned male rats

Jiří Kassaa,*, Jana ®ďárová Karasováb, Kamil Kučac, Kamil Musíleka, Young-Sik Jungd
a Department of Toxicology, Faculty of Military Health Sciences, Hradec Králové, Czech Republic
b Department of Public Health Care, Faculty of Military Health Sciences, Hradec Králové, Czech Republic
c Center of Advanced Studies, Faculty of Military Health Sciences, Hradec Králové, Czech Republic
d Medicinal Science Division, Korea Research Institute of Chemical Technology, Yusong, Daejeon, South Korea

The neuroprotective effects of a novel oxime KR-22934, the oxime K203 and obidoxime in combination with atropine in rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 80% LD50) were studied. The tabun-induced neurotoxicity was monitored at 24 h following tabun challenge using a functional observational battery and an automatic measurement of motor activity. The results indicate that all tabun-poisoned rats treated with oximes in combination with atropine were able to survive within 24 h following tabun poisoning. One tabun-poisoned rat without antidotal treatment died within 24 h. The oximes KR-22934 and K203 combined with atropine showed a similar potency to decrease tabun-induced neurotoxicity at 24 h after tabun administration while the neuroprotective efficacy of obidoxime was slightly higher. However, no oxime was able to eliminate tabun-induced neurotoxicity completely. When atropine was administered alone, negligible neuroprotective efficacy was observed. Based on the results, a novel oxime KR-22934 did not bring any improvement of the neuroprotective efficacy of antidotal treatment of acute tabun poisonings.

Keywords: Tabun; Neurotoxicity; Oximes; Functional observational battery; Rats

Received: February 27, 2013; Revised: April 2, 2013; Accepted: April 3, 2013; Published: April 1, 2014  Show citation

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Kassa J, ®ďárová Karasová J, Kuča K, Musílek K, Jung Y. Comparison of the neuroprotective effects of a novel bispyridinium oxime KR-22934 with the oxime K203 and obidoxime in tabun-poisoned male rats. J Appl Biomed. 2014;12(2):111-117. doi: 10.1016/j.jab.2013.04.002.
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    References

    1. Bajgar, J., 2004. Organophosphate/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv. Clin. Chem. 38, 151-216. Go to original source...
    2. Cabal, J., Bajgar, J., 1999. Tabun - reappearance 50 years later. Chem. Listy 93, 27-31 (in Czech).
    3. Cabal, J., Kuca, K., Kassa, J., 2004. Specification of the structure of oximes able to reactivate tabun inhibited acetylcholinesterase. Pharmacol. Toxicol. 95, 81-86. Go to original source... Go to PubMed...
    4. Cassel, G., Karlsson, L., Waara, L., Wee Ang, K., GoranssonNyberg, A., 1997. Pharmacokinetics and effects of HI-6 in blood and brain of soman-intoxicated rats: a microdialysis study. Eur. J. Pharmacol. 332, 43-52. Go to original source... Go to PubMed...
    5. Delfino, R.T., Ribeiro, T.S., Figueroa-Villar, J.D., 2009. Organophosphorus compounds as chemical warfare agents: a review. J. Braz. Chem. Soc. 20, 407-428. Go to original source...
    6. Dohnal, V., Kuča, K., Jun, D., 2005. Prediction of a new broadspectrum reactivator capable of reactivating acetylcholinesterase inhibited by nerve agents. J. Appl. Biomed. 3, 139-145. Go to original source...
    7. Ekström, F., Akfur, C., Tunemalm, A.K., Lundberg, S., 2006. Structural changes of phenylalanine 338 and histidine 447 revealed by the crystal structures of tabun-inhibited murine acetylcholinesterase. Biochemistry 45, 74-81. Go to original source... Go to PubMed...
    8. Frantik, E., Hornychova, M., 1995. Clustering of neurobehavioral measures of toxicity. Homeostasis 36, 19-25.
    9. Jokanovic, M., Prostran, M., 2009. Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. Curr. Med. Chem. 16, 2177- 2188. Go to original source... Go to PubMed...
    10. Jokanovic, M., Maksimovic, M., Kilibarda, V., Jovanovic, D., Savic, D., 1996. Oxime-induced reactivation of acetycholinesterase inhibited by phosphoramidates. Toxicol. Lett. 85, 35-39. Go to original source... Go to PubMed...
    11. Kassa, J., Krejcova, G., 2003. Neuroprotective effects of currently used antidotes in tabun-poisoned rats. Pharmacol. Toxicol. 92, 258-264. Go to original source... Go to PubMed...
    12. Kassa, J., Kuneąová, G., 2006. Comparison of the neuroprotective effects of the newly developed oximes (K027 K048) with trimedoxime in tabun-poisoned rats. J. Appl. Biomed. 4, 123- 134. Go to original source...
    13. Kassa, J., Cabal, J., Kuca, K., 2005. A comparison of the efficacy of currently available oximes against tabun in rats. Biologia 60 (Suppl. 17) 77-79.
    14. Kassa, J., Karasova, J., Musilek, K., Kuca, K., 2008. An evaluation of therapeutic and reactivating effects of newly developed oximes (K156, K203) with commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice. Toxicology 243, 311-316. Go to original source... Go to PubMed...
    15. Kassa, J., Karasova, J., Vasina, L., Bajgar, J., Kuca, K., Musilek, K., 2009. A comparison of neuroprotective efficacy of newly developed oximes (K203, K206) and commonly used oximes (obidoxime HI-6) in tabun-poisoned rats. Drug Chem. Toxicol. 32, 128-138. Go to original source... Go to PubMed...
    16. Kassa, J., Zdarova Karasova, J., Tesarova, S., Musilek, K., Kuca, K., Jung, Y.S., 2010a. A comparison of neuroprotective efficacy of the oxime K203 and its fluorinated analogue (KR-22836) with obidoxime in tabun-poisoned rats. Bas. Clin. Pharmacol. Toxicol. 107, 861-867. Go to original source...
    17. Kassa, J., Zdarova Karasova, J., Caisberger, F., Musilek, K., Kuca, K., Jung, Y.S., 2010b. A comparison of reactivating and therapeutic efficacy of the oxime K203 and its fluorinated analog (KR-22836) with currently available oximes (obidoxime, trimedoxime, HI-6) against tabun in rats and mice. J. Enzyme Inhib. Med. Chem. 25, 480-484. Go to original source... Go to PubMed...
    18. Kassa, J., Musilek, K., Zdarova Karasova, J., Kuca, K., Bajgar, J., 2012. Two possibilities how to increase the efficacy of antidotal treatment of nerve agent poisonings. Mini-Rev. Med. Chem. 12, 24-34. Go to original source...
    19. Kirk, K.L., 2006. Selective fluorination in drug design and development. An overview of biochemical rationales. Curr. Top. Med. Chem. 6, 1447-1456. Go to original source...
    20. Kuca, K., Bielavsky, J., Cabal, J., Kassa, J., 2003. Synthesis of a new reactivator of tabun inhibited acetylcholinesterase. Bioorg. Med. Chem. Lett. 13, 3545-3547. Go to original source... Go to PubMed...
    21. Kuca, K., Jun, D., Musilek, K., 2006. Structural requirements of acetylcholinesterase reactivators. Mini Rev. Med. Chem. 6, 269-277. Go to original source... Go to PubMed...
    22. Lorke, D.E., Kalasz, H., Petroianu, G.A., Tekes, K., 2008. Entry of oximes into the brain: a review. Curr. Med. Chem. 15, 743- 753. Go to original source...
    23. Lotti, M., 2000. Organophosphorus compounds. In: Spencer, P.S., Schaumburg, H.H. (Eds.), Experimental and Clinical Neurotoxicology. Oxford University Press, New York, pp. 898-925.
    24. McDonough Jr., J.H., Shih, T-M., 1997. Neuropharmacological modulation of nerve agent-induced seizure and neuropathology. Neurosci. Biobehav. Rev. 21, 559-579. Go to PubMed...
    25. Moser, V.C., Tilson, H., McPhail, R.C., Becking, G.C., Cuomo, V., Frantik, E., Kulig, B.M., Winneke, G., 1997. The IPCS collaborative study on neurobehavioral screening methods: II. Protocol design and testing procedures. NeuroToxicology 18, 929-938.
    26. Mueller, K., Faeh, C., Diederich, F., 2007. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881-1886. Go to original source... Go to PubMed...
    27. Musilek, K., Kuca, K., Jun, D., Dolezal, M., 2007. Progress in synthesis of new acetylcholinesterase reactivators in period 1990-2004. Curr. Org. Chem. 11, 229-238. Go to original source...
    28. Puu, G., Artursson, E., Bucht, G., 1986. Reactivation of nerve agent inhibited acetylcholinesterase by HI-6 and obidoxime. Biochem. Pharmacol. 35, 1505-1510. Go to original source...
    29. Roth, Z., Josífko, M., Malý, V., Trčka, V., 1962. Statistical Methods in Experimental Medicine. SZN Praha (in Czech).
    30. Sakurada, K., Matsubara, K., Shimizu, K., Shiono, H., Seto, Y., Tsuge, K., Toshibo, M., Sakai, I., Mukoyama, H., Takatori, T., 2003. Pralidoxime iodide (2-PAM) penetrates across the blood-brain barrier. Neurochem. Res. 28, 1401-1407. Go to original source... Go to PubMed...
    31. Taylor, P., 2001. Anticholinesterase agents. In: Hardman, J.G., Limbird, L.E. (Eds.), The Pharmacological Basis of Therapeutics. McGraw Hill, New York, pp. 175-191.
    32. Wildman, S.A., Crippen, G.M., 1999. Prediction of physicochemical parameters by atomic contribution. J. Chem. Inf. Comput. Sci. 39, 868-873. Go to original source...
    33. Worek, F., Widmann, R., Knopff, O., Szinicz, L., 1998. Reactivating potency of obidoxime, pralidoxime, HI-6 and HLö-7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compounds. Arch. Toxicol. 72, 237-243. Go to original source... Go to PubMed...
    34. Zdarova Karasova, J., Stodulka, P., Pohanka, M., Kuca, K., 2010a. In vitro screening of blood-brain barrier penetration of monoquaternary acetylcholinesterase reactivators. Anal. Lett. 43, 1516-1524. Go to original source...
    35. Zdarova Karasova, J., Pohanka, M., Musilek, K., Zemek, F., Kuca, K., 2010b. Passive diffusion of acetylcholinesterase oxime reactivators through the blood-brain barrier: influence of molecular structure. Toxicol. In Vitro 24, 1838-1844. Go to original source... Go to PubMed...

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