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The novel CGRP receptor antagonist BIBN 4096 BS alleviates a postoperative intestinal inflammation and prevents postoperative ileus
Author(s) -
Glowka T. R.,
Steinebach A.,
Stein K.,
Schwandt T.,
Lysson M.,
Holzmann B.,
Tsujikawa K.,
Jonge W. J.,
Kalff J. C.,
Wehner S.
Publication year - 2015
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.12584
Subject(s) - calcitonin gene related peptide , inflammation , cytokine , medicine , receptor , endocrinology , receptor antagonist , antagonist , neuropeptide
Background Abdominal surgery results in neuronal mediator release and subsequent acute intestinal hypomotility. This phase is followed by a longer lasting inflammatory phase resulting in postoperative ileus ( POI ). Calcitonin gene‐related peptide ( CGRP ) has been shown to induce motility disturbances and in addition may be a candidate mediator to elicit neurogenic inflammation. We hypothesized that CGRP contributes to intestinal inflammation and POI . Methods The effect of CGRP in POI was tested in mice treated with the highly specific CGRP receptor antagonist BIBN 4096 BS and in CGRP receptor‐deficient ( RAMP ‐1 −/− ) mice. POI severity was analyzed by cytokine expression, muscular inflammation and gastrointestinal ( GI ) transit. Peritoneal and muscularis macrophages and mast cells were analyzed for CGRP receptor expression and functional response to CGRP stimulation. Key Results Intestinal manipulation ( IM ) resulted in CGRP release from myenteric nerves, and a concurrent increased interleukin ( IL )‐6 and IL ‐1 β transcription and leukocyte infiltration in the muscularis externa and increased GI transit time. CGRP potentiates IM ‐induced cytokine transcription within the muscularis externa and peritoneal macrophages. BIBN 4096 BS reduced cytokine levels and leukocyte infiltration and normalized GI transit. RAMP 1 −/− mice showed a significantly reduced leukocyte influx. CGRP receptor was expressed in muscularis and peritoneal macrophages but not mast cells. CGRP mediated macrophage activation but failed to induce mast cell degranulation and cytokine expression. Conclusions & Inferences CGRP is immediately released during abdominal surgery and induces a neurogenic inflammation via activation of abdominal macrophages. BIBN 4096 BS prevented IM ‐induced inflammation and restored GI motility. These findings suggest that CGRP receptor antagonism could be instrumental in the prevention of POI .