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ECPB 2017, 78(2): 24–31
Research articles

Action of Cyclooxygenase and Lipoxygenase Inhibitors on Processes on Ulcerogeneis and Cytoprotection in gastric Mucosa of Rats


Nonosteroidal inti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase (COX) – are the most commonly prescribed medications in the treatment of inflammatory states. However their main side effect is associated with the development of peptic ulcers. Lipooxygenase (LOX) pathway also plays an important role in inflammation. Compounds that combine COX and LOX inhibition are potential new drugs to treat the inflammation. It was supposed, that combined inhibition avoids some of the disadvantages of conventional COX-inhibitors in gastro-intestinal system. Another potential approach in the development of safe anti-inflammatory drugs is the creation of hydrogen sulphide (H2S) – releasing analogues of conventional NSAIDs. Beneficial effect in this sphere may by demonstrated by novel compounds, 4-thiazolidinone-based derivatives possessing a dual COX/lLOX inhibitory action and capable to release H2S. Thus, the purpose of this study is to evaluate the action of a novel 4-thiazolidinone derivative, possesing dual COX/LOX inhibitory action on parameters of NO-synthase system and oxidative stress in gastric mucosa of rats. Rats were divided into 4 groups: 1 – control, 2 – 2A5DHT, 3 – Les-5054, 4 – Les-5055. Dual COX/LOX derivatives (2A5DHT, Les-5054 and Les-5055) were introduced in a single dose 10 mg/kg. In gastric mucosa the following parameters were determined: alterations in malonic dialdehyde and H2S concentrations, activities of myeloperoxydase, superoxide dismutase, catalase, inducible and constitutive NO-synthases (iNOS and cNOS). Non of studied 4-thiazolidinone-based derivatives caused formation of gastric lesions, proving decreased gastrotoxicity of dual COX/LOX inhibitors as compared to conventional NSAIDs. However iNOS activity significantly increased in groups treated by 2A5DHT and Les-5055 (by 6,5 and 2-fold correspondently, р ≤ 0,01) indicating pre-inflammatory condition. As a result of the rise in iNOS activity, NO concentration increased in these groups. It was shown that Les- 5054 releases H2S in gastro-intestinal system. In group of Les-5054 treated rats parameters of NO-synthase system and H2S concentration were similar to those in the control group. Dual COX/LOX inhibitor 2A5DHT increased an activity of myeloperoxydase as opposite to Les-5054. It is well known that use of NSAIDs is accompanied by the increase of lipoperoxidation processes and the formation of oxidative stress. I our study all used 4-thiazolidinone-based derivatives didn’t influence malonic dialdehyde concentration, however activity of main antioxidant enzymes superoxide dismutase and catalase increased. It can by explained on one hand by antioxidant properties of studied compounds (2A5DHT, Les-5054 and Les-5054) on the other hand by the inhibition of LOX resulted by reduction of leucotriens production. Obtained results in this research allow us to conclude, that H2S released from Les-5054 played the crucial role in the regulation of iNOS and myeloperoxydase activities. Compounds 2A5DHT, Les-5054 and Les-5055 didn’t change the intensity of lipid peroxydation in gastric mucosa however increased the activity of enzymes of antioxidant protective system (superoxide dismutase and catalase). It proved beneficial effects of dual COX/LOX inhibitors as compared to traditional NSAIDs.

Keywords: hydrogen sulfide, nitric oxide, gastric mucosa, cyclooxygenase, lypoxygenase

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  1. 1. Bychkov M. The factors of risk of gastroesophageal reflux disease in patients with long-lasting taking of the non-steroidal anti-inflammatory drugs. Scientific courier of Uzhgorod University. Ser.: Medicine. 2011;40:50-53.
  2. 2. Denysenko N, Fomenko I, Fedevych Y, Sklyarov O. H2S-releasing non-steroidal anti-inflammatory drug ATB-346 has lower gastrotoxicity compared with structural analogue naproxen. Medical and clinical chemistry. 2014;16(4):26-29.
  3. 3. Zimenkovskyj B, Lesyk R. 4-thiazolodones. Chemistry, physiological action, perspectives. Vinnytsja: New book. 2004:106.
  4. 4. Koroliuk M, Ivanova L, Maĭorova I, Tokarev V. A method of determining catalase activity. Lab Delo. 1988;(1):16-19.
  5. 5. Ravaeva M, Chuyan E. Change of activity system of synthesis nitrogen oxide under action of low-power millimeter waves. Scientific Notes of Taurida V.I. Vernadsky National University. 2011;63(4).201-210.
  6. 6. Timirbulatov R, Seleznev E. Method for increasing the intensity of free radical oxidation of lipid-containing components of the blood and its diagnostic significance Lab Delo. 1981;(4):209-211.
  7. 7. Chevari S, Andial T, Shtrenger Ia.Determination of antioxidant parameters of blood and their diagnostical significance. Lab Delo.1991;(10):9-13.
  8. 8. Badri W, Miladi K, Nazari Q, Greige-Gerges H, Fessi H, Elaissari A. Encapsulation of NSAIDs for inflammation management: Overview, progress, challenges and prospects. Int J Pharm. 2016;515(1-2):757-773.
  9. 9. Basivireddy J, Jacob M, Balasubramanian K. Indomethacin induces free radical-mediated changes in renal brush border membranes. Arch Toxicol. 2005;79(8):441-450.
  10. 10. Bertolini A, Ottani A, Sandrini M. Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: critical remarks. Curr Med Chem. 2002;9(10):1033-1043.
  11. 11. Blackler R, Motta J, Manko A, Workentine M, Bercik P, Surette M et al. Hydrogen sulphide protects against NSAID-enteropathy through modulation of bile and the microbiota. Br J Pharmacol. 2015;172(4):992-1004.
  12. 12. Blackler R, Gemici B, Manko A, Wallace J. NSAID-gastroenteropathy: new aspects of pathogenesis and prevention. Curr. Opin. Pharmacol. 2014;11:11-16.
  13. 13. Bradley P, Christensen R, Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation . Blood. 1982;60:618-622.
  14. 14. Brzozowski T, Konturek P, Pajdo R, Ptak-Belowska A, Kwiecien S, Pawlik M et al. Physiological mediators in nonsteroidal anti-inflammatory drugs (NSAIDs)-induced impairment of gastric mucosal defense and adaptation. Focus on nitric oxide and lipoxins. J Physiol Pharmacol. 2008;2:89-102.
  15. 15. Chan M, Wallace J. Hydrogen sulfide-based therapeutics and gastrointestinal diseases: translating physiology to treatments. Am J Physiol Gastrointest Liver Physiol. 2013;305:G467-G473.
  16. 16. Fiorucci S, Antonelli E, Distrutti E, Rizzo G, Mencarelli A, Orlandi S et al. Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs.Gastroenterology. 2005;129(4):1210-1224.
  17. 17. Fomenko I, Sklyarov A, Bondarchuk T, Biletska L, Panasyuk N, Wallace J. Effects of conventional and hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs in rats with stress-induced and epinephrine-induced gastric damage. Stress. 2014;17(6)
  18. 18. Goldstein J, Cryer B. Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies. Drug Healthc Patient Saf. 2015;7:31-41.
  19. 19. Hickey E, Raje R, Reid V, Gross S, Ray S. Diclofenac induced in vivo nephrotoxicity may involve oxidative stress-mediated massive genomic DNA fragmentation and apoptotic cell death. Free Radic Biol Med. 2001;31(2):139-152.
  20. 20. Lanas A. Role of nitric oxide in the gastrointestinal tract. Arthritis Research & Therapy. 2008;10(2):4-12.
  21. 21. Magierowski M, Magierowska K, Kwiecien S, Brzozowski T. Gaseous mediators nitric oxide and hydrogen sulfide in the mechanism of gastrointestinal integrity, protection and ulcer healing.Molecules. 2015;20(5):9099-9123.
  22. 22. Mollace V, Muscoli C, Masini E, Cuzzocrea S, Salvemini D. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev. 2005;57(2)
  23. 23. Nasadyuk C, Sklyarov A. Thymohexin exhibits cytoprotective effect in experimental gastric lesions in rats both through the inhibition of inducible nitric oxide synthase and reduction of oxidative mucosal damage. Regul Pept. 2013; 180:50-57.
  24. 24. Olkhovskiy O, Zaichko N. Influence propargyl glycine and sodium content of hydrogen and H2S- indices of antioxidant system in the myocardium of rats of different ages. Med Chem. 2013;15(4):10-15.

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