dl-trans-3,4-Dihydroxy-1-selenolane (DHSred) heals indomethacin-mediated gastric ulcer in mice by modulating arginine metabolism

• Published in: Biochimica et biophysica acta Vol. 1840; no. 12; pp. 3385 - 3392
• Main Authors: Chakraborty, Saikat, Yadav, Sudhir K., Subramanian, Mahesh, Iwaoka, Michio, Chattopadhyay, Subrata
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2014
• Subjects: Arginase; arginine; Cytokine balance; cytokines; endothelial nitric oxide synthase; Gastric ulcer healing; Indomethacin; inducible nitric oxide synthase; metabolism; mice; myeloperoxidase; nitric oxide; NOS; polyamines; stomach; stomach ulcers; Arginase; Cytokine balance; Gastric ulcer healing; NOS; Indomethacin
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.09.004

The importance of the arginine metabolism in gastric ulcer-healing is given relatively less attention. Hence the role of controlling this pathway by dl-trans-3,4-dihydroxy-1-selenolane (DHSred) and omeprazole against indomethacin-induced stomach ulceration in mouse was investigated. Swiss albino mice were ulcerated with indomethacin followed by treatment with the test samples, and the activities of myeloperoxidase (MPO), total nitric oxide synthase (NOS) and arginase, the expressions of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and the pro-/anti-inflammatory cytokine levels were assayed. NOS-inhibitors were also used to establish the biochemical mechanism. Indomethacin induced maximum ulceration in mice on the 3rd day, associated with reduced arginase activity, eNOS expression, along with increased MPO and total NOS activities, nitric oxide (NO) generation, iNOS expression, and pro-/anti-inflammatory (Th1/Th2) cytokine ratio. Treatment with DHSred (2.5mgkg−1×3days) restored the cytokine balance to shift the iNOS/NO axis to the arginase/polyamine axis as revealed from the increased arginase activity and eNOS expression, and reduced iNOS expression, total NOS activity and NO level. The ulcer-healing property of DHSred, but not of omeprazole was due to a favorable pro-/anti-inflammatory cytokine ratio that shifted the arginine metabolism to the polyamine pathway and increased the eNOS/iNOS ratio. The healing action of omeprazole was not significantly associated with these parameters. The shift in the ariginine-metabolism from the iNOS/NO axis to the arginase/polyamine axis is guided by Th1/Th2 cytokines ratio and plays an important role in gastric ulcer-healing. The favourable effects of the non-toxic and water-soluble compound, DHSred on these pathways and other COX-dependent and antioxidative parameters suggested it to be a promising anti-ulcer formulation for further studies. •Formulation of dl-trans-3,4-dihydroxy-1-selenolane (DHSred) as a potential anti-ulcer agent against indomethacin-gastropathy.•DHSred switches iNOS/NO to arginase/polyamine pathway and increases gastric eNOS/iNOS ratio.•DHSred alters the arginine metabolism by reducing the Th1/Th2 ratio.