The dissertation is devoted to the evaluation on the mechanisms of action of COX/LOX inhibitors on the morphological state of the small intestine, parameters of the NO-synthase/arginase system, pro-/antioxidant equilibrium in various models of stress in the small intestinal mucosa (SIM) and reduction of their cytotoxic action by modeling of hydrogen sulfide content.
It has been found that the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) with different mechanism of action on the background of water-restraint stress (WRS) during 5 h leads to a disruption of the metabolism of gaseous mediators (NO and H2S) and the development of prooxidant processes in SIM. The most pronounced cytotoxic effect was observed under condition of the nonselective COX-1/COX-2 inhibitor administration - indomethacin, which caused the development of destructive injuries in the distal part of the small intestine on the background of the independent administration and in conjunction with stress. Administration of the COX-2/5-LOX inhibitor compound 2A5DHT in WRS reduced the activity of iNOS (for 23 %, p<0.05), and increased cNOS (for 46 %, p<0.05) and arginase activity (2.1-fold, p<0.01) in SIM, which indicates the role of the lipoxygenase pathway of the arachidonic acid metabolism in the regulation of the NO-synthase system.
Comparing the effect of naproxen and it’s H2S-releasing compound – ATB-346, it should be noted that significant changes in the basic parameters of the NOS/L-Arg/NO system on the background of WRS were not detected and indicate the dominant effect of the base NSAID substance. However, the most pronounced effect of ATB-346 was observed on the activity of MPO, that decreases both in WRS and epinephrine-induced stress conditions (2-fold and 1.7-fold, p<0.01, respectively), revealing the biochemical mechanisms of the relationship between H2S and MPO.
The administration of 4-thiazolidinone derivatives (compounds Les-5054 and Les-5055) on the background of stress, resulted in suppressing the oxidative pathway of L-Arg metabolism, lipoperoxidation processes, and increasing the activity of antioxidant defence enzymes in SIM, indicating a pronounced cytoprotective effect of the investigated compounds.
The ulcerogenic effect of the non-selective COX-1/COX-2 inhibitor indomethacin (at a dose of 35 mg/kg) was shown, which during 72 hours led to the development of structural and hemorrhagic damages in the ileum. At the same time, iNOS activity increased 3 fold (р<0.01) and the content of NO stable metabolites increased 2-fold (р<0.01), cNOS activity decreased more than 2 fold (р<0.01), arginase activity - in 4-fold (р<0.01) in SIM, plasma L-arginine concentration decreased for 33 % (р<0.01) on the background of these conditions compared to the control group values. The triple administration of the 4-thiazolidinone derivatives on the background of indomethacin-induced lesions decreased the total area of destructive lesions in SIM. It was found that administration of H2S releasing compound (Les-5054) decreased iNOS activity for 35 % (р<0.05) and simultaneously increased cNOS, arginase activity and reduced TBA-active products concentration and MPO activity in SIM as compared with independent action of indomethacin.
Introduction of 4-thiazolidinone derivatives (particularly compound Les-5054), as H2S donors, on the background of stress conditions as well as NSAID-induced lesions of the small intestine exhibit pronounced cytoprotective, anti-inflammatory and antioxidant effects and increase H2S concentration, plaing a key role in reduction the enterotoxic effect of nonselective COX inhibitors and stress in the small intestine.
