Calcitonin gene-related peptide and substance P regulate the intestinal radiation response.
OBJECTIVE
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.


METHODS
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.
Wang
Junru
J
Arkansas Cancer Research Center, Little Rock, Arkansas 72205, USA.
Qiu
Xiaohua
X
Kulkarni
Ashwini
A
Hauer-Jensen
Martin
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage* / Q000235:genetics; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007422:Intestines / Q000187:drug effects* / Q000528:radiation effects*; D008297:Male; D015999:Multivariate Analysis; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000819:agonists; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013373:Substance P / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000235:genetics / Q000494:pharmacology; D014965:X-Rays
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D011812:Quinuclidines; D018015:Receptors, Calcitonin Gene-Related Peptide; D018040:Receptors, Neurokinin-1; C068032:GR 73632; C085215:SR 140333; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D000241:Adenosine; C082299:N-((1S,trans)-2-hydroxycyclopentyl)adenosine