Induction of matrix metalloproteinase‐9 and ‐3 in nonsteroidal anti‐inflammatory drug‐induced acute gastric ulcers in mice: regulation by melatonin

Abstract

The pathogenesis of gastric ulcer is associated with remodeling of extracellular matrix (ECM) by various matrix metalloproteinases (MMPs). However, how MMPs are regulated during nonsteroidal anti-inflammatory drug (NSAID)-induced acute gastric ulceration is not well studied. In this study, different NSAIDs (80 mg/kg b.w.) were applied to generate acute gastric ulcer in the BALB/c mouse and the regulation of MMPs were investigated. NSAIDs caused dose-dependent induction in MMP-9 and -3 activities and expressions in ulcerated gastric tissues along with significant infiltration of inflammatory cells and disruption of gastric mucosal layer. In addition, an increase in tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-8 expression, excessive generation of hydroxyl radical ((*)OH), and protein oxidation and lipid peroxidation were observed in acute ulcerated gastric tissues. In this study, the efficacy of melatonin on activities of MMP-9 and -3 during prevention of gastric ulcers was tested. Melatonin at a dose of 60 mg/kg b.w. downregulated MMP-9 and -3 both at the enzyme and protein levels in mouse gastric tissues during prevention as well as healing of acute gastric ulcers. It also blocked oxidative stress via inhibition of protein oxidation, lipid peroxidation, (*)OH generation and SOD-2 expression. Moreover, it suppressed myeloperoxidase activity and expressions of TNF-alpha, IL-1beta and IL-8. This study documents for the first time that induction of MMP-9 and -3 activities accompany NSAID-induced inflammation and oxidative stress in gastric tissues and indicates that, melatonin may be a preventive or therapeutic remedy for gastric ulcers.

Standardized Extract ofBacopa monnieraAttenuates Okadaic Acid Induced Memory Dysfunction in Rats: Effect on Nrf2 Pathway

“…Melatonin (Mel) is an endogenous antioxidant, and its metabolites are potent free radical scavengers, indirect antioxidants [35, 36], and an anti-inflammatory agent [37, 38]. Recently, Melatonin showed protection against exogenous β -amyloid deposition induced mitochondrial dysfunction and other neurodegenerative disease models [39–41].…”

Gene regulation by melatonin linked to epigenetic phenomena

“…Genomic actions of melatonin were further expanded when it was shown that melatonin also ameliorates inflammation by blocking transcriptional factors and inhibiting the transcriptional activation of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1 Sasaki et al, 2002) and inflammatory enzymes such as COX-2, iNOS (Deng et al, 2006;Dong, 2003) and matrix metalloproteinases (MMPs) (Esposito et al, 2008a;Ganguly and Swarnakar, 2009;Swarnakar et al, 2011) by blocking NF-κB binding to DNA (Chuang et al, 1996;Natarajan et al, 1995). Several reports have addressed the mechanisms that are involved in genomic actions of melatonin.…”

Cytoprotective and anti‐inflammatory effects of melatonin in hydrogen peroxide‐stimulated CHON‐001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway

“…In terms of its action on the immune system, melatonin modulates key biological factors, which include inflammatory cytokines [36]. Furthermore, it has been shown that melatonin inhibited in vivo the expression of iNOS in liver and lung of LPS‐treated rats [37], and in carrageenan‐treated rats [38], and downregulated matrix metalloproteinase‐9 and ‐3 in nonsteroidal anti‐inflammatory drug‐induced acute gastric ulcers in mice [39]. In addition, melatonin inhibited LPS‐induced increase of COX‐2 protein expression in RAW 264.7 macrophages [40].…”