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

Abstract

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-1receptor 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-1receptor blockers as protectors against intestinal toxicity during radiation therapy and after nontherapeutic radiation exposure are warranted.

Radiation enteropathy—pathogenesis, treatment and prevention

“…Many pharmacological and genetic models also showed that the relationship cannot be explained simply by consequential late effects, for example, mast cell deficient rats, sensory nerve-ablated rats, and TGF-beta heterozygous rats all show dissociations between early and delayed injury 26–29 , i.e. , all have exacerbated epithelial injury, but reduced levels of intestinal fibrosis.…”

Preclinical Research into Basic Mechanisms of Radiation-Induced Heart Disease

“…Interestingly, both downregulation of TNF- α and upregulation of IGF-1 are associated with reduced normal tissue radiation injury [112, 113]. In line with this evidence, CGRP has been shown to protect in a rat model of radiation enteropathy [114]. Its role in RIHD has not yet been studied extensively.…”

Potential Targets for Intervention in Radiation-Induced Heart Disease

“…The roles of the two sensory neuropeptides CGRP and substance P have been studied extensively in a rat model of radiation enteropathy [135]. Small intestine mRNA levels of both neuropeptides were upregulated after local irradiation.…”

“…Administration of CGRP ameliorated radiation-induced intestine injury in rats, while a CGRP antagonist exacerbated injury, suggesting that CGRP played a protective role. Opposing results were obtained from the administration of substance P and a substance P receptor antagonist, suggesting that substance P played an aggravating role in intestinal radiation injury [135]. Considering the mast cell involvement in radiation-induced upregulation of CGRP in experimental RIHD and the known protective roles of CGRP in experimental radiation enteropathy and in myocardial injury from other causes, the role of this neuropeptide in RIHD deserves further investigation.…”