Stress-induced gastric ulcer and matrix metalloproteinases: Melatonin as rescuer

Abstract

Stress causes the generation of oxidative bursts that are accompanied by inflammation in different tissues, including gastric tissues.¹ Over the period of two decades, my laboratory and others have reported the involvement of matrix metalloproteases (MMPs), mainly MMP-9 and -3 upregulation, in gastric ulcers developed by non-steroidal anti-inflammatory drugs (NSAIDs), H. pylori infection and stress.^2–5 The excess gastric oxidative damage and MMP-3-dependent gastric inflammation played significant roles in stress-induced gastric mucosal injury.⁴ Moreover, the production of reactive oxygen species (ROS) is associated with mitochondrial dysfunction and apoptosis of gastric mucosal cells as assessed by depolarization of mitochondrial Δψm, caspase activity, and Bax protein expression in stress-induced gastric tissues of mice. Furthermore, stimulating redox-sensitive p38 and activating TNF-α and NF-κB caused MMP-3 and -9 upregulation at protein and activity levels in stress-induced ulcers. Experiments were performed to prevent stress ulcers by a small molecule named melatonin, a hormone having antioxidant and anti-inflammatory activity. Melatonin exerted MMP-3 inhibitory activity in an animal model of swim stress-induced gastric ulcer, which was supported by molecular dynamics simulations studies of the MMP-3-melatonin complex.⁴ Oxidative stress-induced damage was protected significantly better by melatonin-loaded nanocapsules (MNCs) as compared to free melatonin in cell culture systems.⁶ Additionally, restrained cold stress-induced gastric ulcers reduced MMP-2 activity that perturbs extracellular matrix rearrangement in gastric tissues. The drug omeprazole restored MMP-2 activity by binding with the MMP-2/TIMP-2 complex, thus maintaining the protease/anti-protease ratio while inhibiting gastric ulcers.⁷ Herein, the mechanism of stress-induced gastric ulcer, the involvement of MMPs thereon, and the role of melatonin in modulating MMP activity are discussed.