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Calcitonin Gene-Related Peptide and Substance P Regulate the Intestinal Radiation Response

Authors' Affiliation: Arkansas Cancer Research Center, Departments of Surgery and Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

Requests for reprints: Martin Hauer-Jensen, Arkansas Cancer Research Center, 4301 West Markham, Slot 725, Little Rock, AR 72205. Phone: 501-686-7912; Fax: 501-686-7861; E-mail: mhjensen{at}life.uams.edu.

Purpose: Intestinal toxicity is important in the therapeutic use of radiation as well as in nontherapeutic radiation exposure scenarios. Enteric sensory nerves are critical for mucosal homeostasis and for an appropriate response to injury. This study assessed the role of the two major neuropeptides released by sensory nerves, calcitonin gene-related peptide (CGRP) and substance P, in the intestinal radiation response.

Experimental Design: Male rats received full-length CGRP, CGRP antagonist (CGRP_8-37), a modified substance P peptide (GR73632), a small-molecule substance P receptor antagonist (neurokinin-1 receptor antagonist, SR140333), or vehicle for 2 weeks after localized X irradiation of a 4-cm loop of small bowel. Structural, cellular, and molecular aspects of the intestinal radiation response were assessed.

Results: Intestinal CGRP and substance P transcript levels increased after irradiation. Multivariate analysis showed that CGRP and SR140333 ameliorated and CGRP_8-37 and GR73632 exacerbated intestinal radiation injury. Univariate analysis revealed increased radiation injury score, bowel wall thickening, and collagen III deposition after treatment with CGRP_8-37, whereas SR140333 ameliorated radiation injury score, loss of mucosal surface area, collagen III deposition, and mucosal inflammation.

Conclusions: The two major neuropeptides released by sensory neurons, CGRP and substance P, are overexpressed after irradiation and have opposing effects during development of intestinal radiation injury. Systematic studies to assess CGRP agonists and/or neurokinin-1 receptor blockers as protectors against intestinal toxicity during radiation therapy and after nontherapeutic radiation exposure are warranted.

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				J Wang and M Hauer-Jensen Neuroimmune interactions: potential target for mitigating or treating intestinal radiation injury Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S41 - S48. [Abstract] [Full Text] [PDF]