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Digestive Diseases and Sciences
Erschienen in: Digestive Diseases and Sciences 6/2014

01.06.2014 | Original Article

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

verfasst von: Takuya Inoue, Masaaki Higashiyama, Izumi Kaji, Sergiy Rudenkyy, Kazuhide Higuchi, Paul H. Guth, Eli Engel, Jonathan D. Kaunitz, Yasutada Akiba

Erschienen in: Digestive Diseases and Sciences | Ausgabe 6/2014

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Abstract

Backgrounds and Aims

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.

Conclusion

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.
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Metadaten
Titel
Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats
verfasst von
Takuya Inoue
Masaaki Higashiyama
Izumi Kaji
Sergiy Rudenkyy
Kazuhide Higuchi
Paul H. Guth
Eli Engel
Jonathan D. Kaunitz
Yasutada Akiba
Publikationsdatum
01.06.2014
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 6/2014
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-013-3001-6

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