Role of Dopamine and D2 Dopamine Receptor in the Pathogenesis of Inflammatory Bowel Disease
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VEGF-induced vascular permeability and blood vessels remodeling are key features of inflammatory bowel disease (IBD) pathogenesis. Dopamine through D2 receptor (D2R) inhibits VEGF/VPF-mediated vascular permeability and angiogenesis in tumor models. In this study, we tested the hypothesis that pathogenesis of IBD is characterized by the disturbance of dopaminergic system and D2R activity.
IL-10 knockout (KO) mice and rats with iodoacetamide-induced ulcerative colitis (UC) were treated intragastrically with D2R agonists quinpirole (1 mg/100 g) or cabergoline (1 or 5 µg/100 g). Macroscopic, histologic, and clinical features of IBD, colonic vascular permeability, and angiogenesis were examined.
Although colonic D2R protein increased, levels of tyrosine hydroxylase and dopamine transporter DAT decreased in both models of IBD. Treatment with quinpirole decreased the size of colonic lesions in rats with iodoacetamide-induced UC (p < 0.01) and reduced colon wet weight in IL-10 KO mice (p < 0.05). Quinpirole decreased colonic vascular permeability (p < 0.001) via downregulation of c-Src and Akt phosphorylation. Cabergoline (5 µg/100 g) reduced vascular permeability but did not affect angiogenesis and improved signs of iodoacetamide-induced UC in rats (p < 0.05).
Treatment with D2R agonists decreased the severity of UC in two animal models, in part, by attenuation of enhanced vascular permeability and prevention of excessive vascular leakage. Hence, the impairment dopaminergic system seems to be a feature of IBD pathogenesis.
KeywordsInflammatory bowel disease Animal models Dopamine D2 dopamine receptor Vascular permeability
The present study was supported by a Department of Veterans Affairs, Veterans Health Administration Merit Review Grant VAMR0710-580 and VAMR0810-877 to Zs. Sandor and S. Szabo and by U.S. Civilian Research & Development Foundation (CRDF) CREST II Junior Scientist Research Collaboration Program 09DP036-05 and the Ministry of Education and Science of Ukraine Grant 15BF036-01 to G. Tolstanova
Conflict of interest
- 35.Gomez R, Gonzalez-Izquierdo M, Zimmermann RC, et al. Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model. Endocrinology. 2006;147:5400–5411.CrossRefPubMedGoogle Scholar
- 42.Eldrup E, Richter EA, Christensen NJ. DOPA, norepinephrine, and dopamine in rat tissues: no effect of sympathectomy on muscle DOPA. Am J Physiol. 1989;256:284–287.Google Scholar
- 43.Mezey E, Eisenhofer G, Hansson S, et al. Non-neuronal dopamine in the gastrointestinal system. Clin Exp Pharmacol Physiol Suppl. 1999;26:14–22.Google Scholar
- 46.Li ZS, Schmauss C, Cuenca A, et al. Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out mice. J Neurosci. 2006;26:2798–2807.CrossRefPubMedGoogle Scholar
- 49.Eldrup E, Richter EA. DOPA, dopamine, and DOPAC concentrations in the rat gastrointestinal tract decrease during fasting. Am J Physiol Endocrinol Metab. 2000;279:815–822.Google Scholar
- 52.Tarnawski A, Coron E, Mosnier JF, et al. In-vivo detection by confocal endomicroscopy of two distinct structural abnormalities in angioarchitecture and increased VP in colonic mucosa of patients with IBD in remission: mechanistic implications. Gastroenterology. 2009;136:112.Google Scholar