Upregulation of collagenase-1 and -3 in indomethacin-induced gastric ulcer in diabetic rats: role of melatonin.

Collagenases are key proteases involved in inflammation and injury. We addressed whether collagenases have an association with the susceptibility of gastric injury under diabetes as well as the effect of melatonin on collagenases in ulcerated gastric tissues. Diabetes was induced in rats by a single dose of streptozotocin (STZ) followed by gastric ulceration using indomethacin, and melatonin's action was studied by its application prior to indomethacin exposure. Ulcer indices and damage were elevated significantly in gastric tissues of diabetic compared with nondiabetic rats. Melatonin reversed the effect of indomethacin during protection of gastric ulcers in diabetic rats. Matrix metalloproteinase (MMP)-13 (i.e., collagenase-3) was upregulated in diabetic gastric mucosa and enhanced further upon ulceration while melatonin ameliorated their activity. In addition, gastric tissues showed enhanced expression of both MMP-1 (i.e., collagenases-1) and -13 significantly in diabetic rats compared with nondiabetic animals and more so during ulceration while tissue inhibitors of metalloproteinase-1 (TIMP-1) showed an opposite trend. MMP-2 activities exhibited a ∼50% downregulation during gastric ulceration which were rescued by melatonin. Moreover, increased expression of both MMP-1 and -13 was mediated by activator protein-1 activation via extracellular signal-regulated kinase 1/2 which were parallel to upregulation of tumor necrosis factor-α, interleukin-1β, and heat shock protein-70 during ulceration. Melatonin arrested collagenase expression by downregulation of these signaling molecules thereby halting the progression of the disease. We conclude that diabetic gastric tissues are susceptible to ulceration and associated with MMP-1 and -13 upregulation in indomethacin-induced injury. Additionally, melatonin protects the gastric damage under diabetes via regulation of both MMP-1 and -13.