title: Dipeptidyl peptidase IV inhibition prevents the formation and promotes the healing of indomethacin-induced intestinal ulcers in rats.
abstract: OBJECTIVE
  We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury.
  
  
  METHODS
  Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. L-Alanine (L-Ala) and inosine 5'-monophosphate (IMP) were co-administered ig after the treatment.
  
  
  RESULTS
  Indomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or L-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and L-Ala + IMP further accelerated intestinal ulcer healing.
  
  
  CONCLUSIONS
  DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Inoue
authors.forename: Masaaki
authors.initials: M
authors.lastname: Higashiyama
authors.forename: Izumi
authors.initials: I
authors.lastname: Kaji
authors.forename: Sergiy
authors.initials: S
authors.lastname: Rudenkyy
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Higuchi
authors.forename: Paul H
authors.initials: PH
authors.lastname: Guth
authors.forename: Eli
authors.initials: E
authors.lastname: Engel
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kaunitz
authors.forename: Yasutada
authors.initials: Y
authors.lastname: Akiba
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D053767:Glucagon-Like Peptide 2 / Q000008:administration & dosage / Q000627:therapeutic use; D007213:Indomethacin / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007291:Inosine Monophosphate / Q000008:administration & dosage / Q000627:therapeutic use; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D014456:Ulcer / Q000517:prevention & control*
chemical_list: C494668:(S)-1-(4-methyl-1-(2-pyrimidinyl)-4-piperidylamino)acetyl-2-pyrrolidinecarbonitrile; D000894:Anti-Inflammatory Agents, Non-Steroidal; D054873:Dipeptidyl-Peptidase IV Inhibitors; D053767:Glucagon-Like Peptide 2; D009570:Nitriles; D010446:Peptide Fragments; D011759:Pyrrolidines; C451520:glucagon-like peptide-2 (3-33); D007291:Inosine Monophosphate; D000409:Alanine; D007213:Indomethacin