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ECPB 2017, 78(2): 24–31
https://doi.org/10.25040/ecpb2017.02.024
Research articles

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

І. FOMENKO, P. SKLYAROV, R. LESYK
Abstract

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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