Protective Roles of α-Calcitonin and β-Calcitonin Gene-Related Peptide in Spontaneous and Experimentally Induced Colitis
Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, USA. Digestive Diseases and Sciences
(Impact Factor: 2.61).
02/2008; 53(1):229-41. DOI: 10.1007/s10620-007-9848-7
Calcitonin gene-related peptide (CGRP) is thought to be involved in the regulation of gastric and mesenteric blood flow, in the control of gastric acid secretion and in the modulation of intestinal motility, yet the precise physiological roles of CGRP remain to be elucidated. To further examine the role(s) of CGRP in gastrointestinal function, we examined mutant mice lacking alphaCGRP or betaCGRP expression. Mutant mice did not demonstrate any overt phenotypic changes, yet exhibited a spontaneous, adult-onset colitis and increased colonic damage using a dextran sulfate sodium model of experimental colitis. Surprisingly, mice lacking betaCGRP show no obvious alterations in CGRP immunoreactivity in the gut, accompanied by an increase in alphaCGRP messenger RNA expression, suggesting an adaptive mechanism to compensate for the lack of betaCGRP. These data demonstrate that both alphaCGRP and betaCGRP play a protective role in the generation of spontaneous colitis, supporting a role for both extrinsic and intrinsic CGRP-containing neurons.
Available from: John Raymond Grider
- "The involvement of CGRP in inflammatory conditions has been extensively studied. Previous studies utilizing CGRP knockout mice (Zhang et al., 2001, Thompson et al., 2008) or a CGRP receptor antagonist (Plourde, et al., 1997; Delafoy et al., 2006) demonstrated a protective role of CGRP in experimentally-induced colitis and a role in mediating inflammation-induced hyperalgesia, visceromoter reflex and colonic hypersensitivity in rats with colonic inflammation. However, the central role of CGRP in inflammatory bowel disease is unknown. "
[Show abstract] [Hide abstract]
ABSTRACT: Previous study has shown that colitis-induced increases in calcitonin gene-related peptide (CGRP) immunoreactivity in bladder afferent neurons result in sensory cross-sensitization. To further determine the effects of colitis on CGRP expression in neurons other than bladder afferents, we examined and compared the levels of CGRP mRNA and immunoreactivity in the lumbosacral dorsal root ganglia (DRG) and spinal cord before and during colitis in rats. We also examined the changes in CGRP immunoreactivity in colonic afferent neurons during colitis. Results showed increases in CGRP mRNA levels in L1 (2.5-fold, p<0.05) and S1 DRG (1.9-2.4-fold, p<0.05). However, there were no changes in CGRP mRNA levels in L1 and S1 spinal cord during colitis. CGRP protein was significantly increased in L1 (2.5-fold increase, p<0.05) but decreased in S1 (50% decrease, p<0.05) colonic afferent neurons, which may reflect CGRP release from these neurons during colitis. In L1 spinal cord, colitis caused increases in the number of CGRP nerve fibers in the deep lamina region extending to the gray commissure where the number of phospho-Akt neurons was also increased. In S1 spinal cord, colitis caused the increases in the intensity of CGRP fibers in the regions of dorso-lateral tract, and caused the increases in the level of phospho-Akt in the superficial dorsal horn of the spinal cord. In spinal cord slice culture, exogenous CGRP increased the phosphorylation level of Akt but not the phosphorylation level of extracellular-signal regulated kinase ERK1/2 even though our previous studies showed that colitis increased the phosphorylation level of ERK1/2 in L1 and S1 spinal cord. These results suggest that CGRP is synthesized in the DRG and may transport to the spinal cord where it initiates signal transduction during colitis.
[Show abstract] [Hide abstract]
ABSTRACT: High is the incidence of gastrointestinal dysfunction induced by cerebrovascular disease. However, little is known about the effects of CGRP on gastrointestinal injuries induced by cerebrovascular disease. The purpose of the present study was to investigate the protective effects of calcitonin gene-related peptide (CGRP) on gastric mucosa injury after focal cerebral ischemia reperfusion in rats. Thirty healthy adult male Wistar rats were selected for this experiment and were randomly divided into CGRP-treated, sham-operated, and control groups, respectively. Ten rats were involved in each group. Focal cerebral ischemia reperfusion rat model was established by a 2-hour left middle cerebral artery occlusion (MCAO) using an intraluminal filament, followed by 46h of reperfusion. CGRP (1 microg/ml) at the dose of 3 microg/kg was injected intraperitoneally (i.p.) at the beginning of reperfusion for rats in CGRP-treated group. Saline as vehicle (3 ml/kg body weight), i.p., was administered at the beginning of reperfusion for rats in control group. Sham-operated animals were subjected to an operation without MCAO. Forty-eight hours after operation, the samples were taken out and processed for calculating stomach mucous membrane damage index according to Guth method, detecting pathological changes of gastric mucosa tissue by light microscopy, determining mast cell distribution by toluidine blue staining, and observing the expression of gastrin (Gas), somatostatin (SST), aquaporin-4 (AQP4), and basic fibroblast growth factor (bFGF) by immunohistochemical staining. The results showed that: (1) Gastric mucosa with diffuse edema, splinter hemorrhage and erosion, numerous endothelial cells necrosis, mucosa dissociation, infiltration of inflammatory cells were observed in both control and CGRP-treated animals. CGRP administration could reduce the damage of gastric mucosa. The injury index of gastric mucosa was lower in CGRP-treated group as compared with that in control group (P<0.05). (2) Gas expression in gastric antrum mucosa was lower in CGRP-treated group than that in control group (P<0.01). SST expression in gastric antrum mucosa was higher in CGRP-treated group than that in control group (P<0.01). AQP4 expression in gastric mucosa was lower in CGRP-treated group than that in control group (P<0.05). bFGF expression in gastric mucosa was higher in CGRP-treated group than that in control group (P<0.01). (3) The mast cell degranulation ratio in control group in gastric mucosa was significantly higher than that in CGRP-treated group (P<0.01). It is concluded that CGRP can regulate the secretion of Gas, SST, AQP(4), and bFGF, inhibit mast cell degaranulation and thus alleviate the damage of gastric mucosa induced by cerebral ischemia and reperfusion. CGRP may be one of the good candidates of potential clinical therapy drugs for regulating gastric mucosal protection and maintaining gastric mucosal integrity after cerebral ischemia and reperfusion.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.