Abstract | BACKGROUND:
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. METHODS:
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. RESULTS: 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). CONCLUSIONS: 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.
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Authors | Ganna Tolstanova, Xiaoming Deng, Amrita Ahluwalia, Brankica Paunovic, Alona Prysiazhniuk, Lyudmyla Ostapchenko, Andrzej Tarnawski, Zsuzsanna Sandor, Sandor Szabo |
Journal | Digestive diseases and sciences
(Dig Dis Sci)
Vol. 60
Issue 10
Pg. 2963-75
(Oct 2015)
ISSN: 1573-2568 [Electronic] United States |
PMID | 25972152
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Ergolines
- Inflammation Mediators
- Receptors, Dopamine D2
- Interleukin-10
- Quinpirole
- Cabergoline
- Dopamine
- Iodoacetamide
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Topics |
- Animals
- Biopsy, Needle
- Blotting, Western
- Cabergoline
- Capillary Permeability
(drug effects)
- Colitis, Ulcerative
(chemically induced, drug therapy, pathology)
- Disease Models, Animal
- Dopamine
(metabolism)
- Ergolines
(pharmacology)
- Female
- Humans
- Immunohistochemistry
- Inflammation Mediators
(metabolism)
- Inflammatory Bowel Diseases
(chemically induced, drug therapy, pathology)
- Interleukin-10
(metabolism)
- Iodoacetamide
(pharmacology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Quinpirole
(pharmacology)
- Random Allocation
- Rats
- Rats, Sprague-Dawley
- Receptors, Dopamine D2
(metabolism)
- Statistics, Nonparametric
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