Original Article
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jul 28, 2011; 17(28): 3310-3321
Published online Jul 28, 2011. doi: 10.3748/wjg.v17.i28.3310
Doxycycline blocks gastric ulcer by regulating matrix metalloproteinase-2 activity and oxidative stress
Laishram Pradeepkumar Singh, Amartya Mishra, Debjit Saha, Snehasikta Swarnakar
Laishram Pradeepkumar Singh, Amartya Mishra, Debjit Saha, Snehasikta Swarnakar, Department of Physiology, Drug Development Diagnostics and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata-700032, India
Author contributions: Singh LP and Mishra A performed all the experiments and wrote the manuscript; Saha D was involved in editing the manuscript and performed a few of the experiments; Swarnakar S designed the study and corrected the manuscript.
Supported by Research Fellowship from Council of Scientific and Industrial Research, New Delhi, No. NBA2007 of DBT, IAP001 and CLP 261 of NTRF
Correspondence to: Dr. Snehasikta Swarnakar, PhD, Head, Department of Physiology, Drug Development Diagnostics and Biotechnology Division, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India. snehasiktas@hotmail.com
Telephone: +91-33-24995759 Fax: +91-33-24735197
Received: June 11, 2010
Revised: December 19, 2010
Accepted: December 26, 2010
Published online: July 28, 2011
Abstract

AIM: To examine the effect of doxycycline on the activity of matrix metalloproteinases (MMPs) and oxidative stress in gastric tissues of rats following gastric injury.

METHODS: Gastric ulcers were generated in rats by administration of 70% ethanol, and activity of doxycycline was tested by administration 30 min prior to ethanol. Similarly, the effect of doxycycline was tested in an indomethacin-induced gastric ulcer model. The activities and expression of MMPs were examined by zymography and Western blot analysis.

RESULTS: Gastric injury in rats as judged by elevated ulcer indices following exposure to ulcerogen, either indomethacin or ethanol, was reversed significantly by doxycycline. Indomethacin-induced ulcerated gastric tissues exhibited about 12-fold higher proMMP-9 activity and about 5-fold higher proMMP-3 activity as compared to control tissues. Similarly, ethanol induced about 22-fold and about 6-fold higher proMMP-9 and proMMP-3 activities, respectively, in rat gastric tissues. Both proMMP-9 and MMP-3 activities were markedly decreased by doxycycline in ulcerogen treated rat gastric tissues. In contrast, the reduced MMP-2 activity in ulcerated tissues was increased by doxycycline during ulcer prevention. On the other hand, doxycycline inhibited significantly proMMP-9, -2 and -3 activities in vitro. In addition, doxycycline reduced oxidative load in gastric tissues and scavenged H2O2in vitro. Our results suggest a novel regulatory role of doxycycline on MMP-2 activity in addition to inhibitory action on MMP-9 and MMP-3 during prevention of gastric ulcers.

CONCLUSION: This is the first demonstration of dual action of doxycycline, that is, regulation of MMP activity and reduction of oxidative stress in arresting gastric injury.

Keywords: Doxycycline; Extracellular matrix; Matrix metalloproteinases; Reactive oxygen species; Tissue inhibitor of metalloproteinase