title: Doxycycline blocks gastric ulcer by regulating matrix metalloproteinase-2 activity and oxidative stress.
abstract: OBJECTIVE
  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 H₂O₂ in 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology, Drug Development Diagnostics and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata-700032, India.
authors.forename: Laishram Pradeepkumar
authors.initials: LP
authors.lastname: Singh
authors.forename: Amartya
authors.initials: A
authors.lastname: Mishra
authors.forename: Debjit
authors.initials: D
authors.lastname: Saha
authors.forename: Snehasikta
authors.initials: S
authors.lastname: Swarnakar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use; D004792:Enzyme Precursors / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D000431:Ethanol; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline; D007213:Indomethacin