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Hydrogen sulfide donors as potential drug-like compounds with anti-inflamatory activity

Work number - M 26 FILED

Presented Danylo Halytsky Lviv National Medical University

1. DENYSENKO Natalia – PhD, Assistant Professor of the Department of Biological Chemistry of Danylo Halytsky Lviv National Medical University
2. LOZYNSKA Iryna – PhD, Assistant Professor of the Department of Biological Chemistry of Danylo Halytsky Lviv National Medical University

The aim of this study was to investigate the mechanism of action of cyclooxygenase (COX) and lipoxygenase (LOG) inhibitors on the morphological state and biochemical parameters of the mucous membranes of small and large intestines and to establish the role of hydrogen sulfide in the mechanisms of cytoprotection in digestive organs. It was noted that nonselective inhibition of COX by indomethacin and naproxen was accompanied with the mucosal damage in the small and large intestine, which are confirmed macroscopically under the conditions of colitis and histologically under the conditions of stress. However, dual inhibition of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism by 2A5DHT reduced the activity of iNOS, myeloperoxidase, and the level of TBA-active products. Whereas the administration of other COX/LOX inhibitors was accompanied by a decrease in hydrogen sulfide concentration in blood plasma compared with controls.

The use of ATB-346 (H2S-containing naproxen) under stress conditions led to the restoration of H2S in blood plasma. Administration of ATB-346 and 4-thiazolidinone derivatives (Les-5054 and Les-5055) was accompanied by an increase in mucus production in the small intestine, due to the release of a gaseous mediator, which consequently increased epithelial proliferation. However, comparing the parameters of the NO-synthase/arginase system and lipoperoxidation processes under the action of naproxen and its H2S-containing analogue during the action of stress, no significant changes were found. This indicates the dominance of the effect of the parental molecule of nonsteroidal anti-inflammatory drug. The cytoprotective effect of NaSH in the mucous membrane of the colon under the conditions of stress and experimental colitis was confirmed by a decrease of cytokine-induced enzymes.

Study of the biological activity allowed identifying hit-compounds among 4-thiazolidinone derivatives, administration of them under stress conditions and indomethacin-induced lesions reduce the activity of proinflammatory enzymes and lipoperoxidation processes in the lower digestive tract and increase hydrogen sulfide level, that indicates the prominence of this class of compounds in the search for new anti-inflammatory drugs. The obtained conclusions may be used as data for the in-depth studies as well as search for novel potentially active anti-inflammatory drugs with reduced ulcerogenic effects on the digestive system.

Number of publications: 14 articles (8 - in peer-reviewed journals). The total number of references of the authors' publications/h-index, according to the databases: Web of Science – 6/2, Scopus – 26/3, Google Shcolar – 62/4. 1 Patent of Ukraine had been received.