Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis.
OBJECTIVE
The gastrointestinal tract is known to be rich in neural systems, among which afferent neurons are reported to exhibit protective actions. We tested whether an endogenous neuropeptide, calcitonin gene-related peptide (CGRP), can prevent gastric mucosal injury elicited by ethanol and enhance healing of acetic acid-induced ulcer using CGRP knockout mice (CGRP(-/-)).


METHODS
The stomach was perfused with 1.6 mmol/L capsaicin or 1 mol/L NaCl, and gastric mucosal injury elicited by 50% ethanol was estimated. Levels of CGRP in the perfusate were determined by enzyme immunoassay. Gastric ulcers were induced by serosal application of absolute acetic acid.


RESULTS
Capsaicin inhibited injured area dose-dependently. Fifty percent ethanol containing capsaicin immediately increased intragastric levels of CGRP in wild-type (WT) mice, although 50% ethanol alone did not. The protective action of capsaicin against ethanol was completely abolished in CGRP(-/-). Preperfusion with 1 mol/L NaCl increased CGRP release and reduced mucosal damage during ethanol perfusion. However, 1 mol/L NaCl was not effective in CGRP(-/-). Healing of ulcer elicited by acetic acid in CGRP(-/-) mice was markedly delayed, compared with that in WT. In WT, granulation tissues were formed at the base of ulcers, and substantial neovascularization was induced, whereas those were poor in CGRP(-/-). Expression of vascular endothelial growth factor was more markedly reduced in CGRP(-/-) than in WT.


CONCLUSIONS
CGRP has a preventive action on gastric mucosal injury and a proangiogenic activity to enhance ulcer healing. These results indicate that the CGRP-dependent pathway is a good target for regulating gastric mucosal protection and maintaining gastric mucosal integrity.
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Takashi
T
Ohno
Youichiro
Y
Hattori
Rie
R
Komine
Takako
T
Ae
Sumito
S
Mizuguchi
Katsuharu
K
Arai
Takeo
T
Saeki
Tatsunori
T
Suzuki
Kanako
K
Hosono
Izumi
I
Hayashi
Yoshio
Y
Oh-Hashi
Yukiko
Y
Kurihara
Hiroki
H
Kurihara
Kikuko
K
Amagase
Susumu
S
Okabe
Katsunori
K
Saigenji
Masataka
M
Majima
D019342:Acetic Acid; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D002211:Capsaicin / Q000627:therapeutic use; D004195:Disease Models, Animal; D000431:Ethanol; D005753:Gastric Mucosa / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D018689:Sensory System Agents / Q000627:therapeutic use; D012965:Sodium Chloride / Q000627:therapeutic use; D013276:Stomach Ulcer / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control
D018689:Sensory System Agents; D000431:Ethanol; D012965:Sodium Chloride; D015740:Calcitonin Gene-Related Peptide; D019342:Acetic Acid; D002211:Capsaicin