Abstract
Matrix metalloproteinases (MMPs) are suggested to play a critical role in extracellular matrix degradation and remodeling during inflammation and wound healing processes. However, the role of MMPs in indomethacin-induced gastric ulcer and its healing process are not clearly understood. This study is aimed at determining the regulation of MMP-9 and -2 activities in indomethacin-induced acute gastric ulceration and healing. Indomethacin-ulcerated stomach extracts exhibit significant up-regulation of pro-MMP-9 (92 kDa) activity and moderate reduction of MMP-2 activity, which strongly correlate with indomethacin dose and severity of ulcer. The anti-inflammatory and antioxidant properties of curcumin, an active component of turmeric, suggest that curcumin may exert antiulcer activity through scavenging reactive oxygen species, by regulating MMP activity, or both. To test these possibilities, the effect of curcumin in indomethacin-induced gastric ulcer is examined by biochemical and histological methods. The results show that curcumin exhibits potent antiulcer activity in acute ulcer in rat model by preventing glutathione depletion, lipid peroxidation, and protein oxidation. Denudation of epithelial cells during damage of gastric lumen is reversed by curcumin through re-epithelialization. Furthermore, both oral and intraperitoneal administration of curcumin blocks gastric ulceration in a dose-dependent manner. It accelerates the healing process and protects gastric ulcer through attenuation of MMP-9 activity and amelioration of MMP-2 activity. Omeprazole, an established antiulcer drug does not inhibit MMP-9 while protecting indomethacin-induced gastric ulcer. We conclude that antiulcer activity of curcumin is primarily attributed to MMP-9 inhibition, one of the major path-ways of ulcer healing.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs),1 stress, and Helicobacter pylori are the major causative factors for gastric ulcer where extracellular matrix (ECM) degradation
Indomethacin-induced suppression of endogenous prostaglandin E production is associated with the inhibition of pro-Matrix metalloproteinases (MMPs)-9 and the decrease of MMP-9 activity [31, 32]
Evidence has been provided to show that IL-1-mediated pro-MMP-9 production is enhanced by indomethacin and that tumor necrosis factor-␣ induces the expression of MMP-9 via the NF-B-mediated pathway [33, 34]
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs), stress, and Helicobacter pylori are the major causative factors for gastric ulcer where extracellular matrix (ECM) degradation. Very little is known about the involvement of MMP and TIMP expression in NSAID-induced gastric ulcer [12,13,14,15]. Mori et al [17] reported MMP-9 induction through activation of NF-B in H. pylori-infected cultured gastric mucosal cells. Literature is very scanty regarding the role of MMPs and TIMPs during the healing process of the gastric ulcer [18]. The roles of MMPs in ulcer development and healing have been demonstrated only in the acetic acid-induced gastric ulcer model [18]. Effect of Curcumin on MMPs in Gastric Ulcer during indomethacin-induced gastric ulceration and its healing by curcumin
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