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Role of Dopamine and D2 Dopamine Receptor in the Pathogenesis of Inflammatory Bowel Disease

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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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Acknowledgments

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

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Authors and Affiliations

  1. VA Long Beach Healthcare System, Departments of Medicine, Pathology and Pharmacology, VA Medical Center (05/113), University of California-Irvine, 5901 East 7th Street, Long Beach, CA, 90822, USA

    Ganna Tolstanova, Xiaoming Deng, Amrita Ahluwalia, Brankica Paunovic, Andrzej Tarnawski, Zsuzsanna Sandor & Sandor Szabo

  2. Educational-Scientific Center “Institute of Biology”, Taras Shevchenko National University of Kyiv, Kiev, Ukraine

    Ganna Tolstanova, Alona Prysiazhniuk & Lyudmyla Ostapchenko

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  1. Ganna Tolstanova
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  2. Xiaoming Deng
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  3. Amrita Ahluwalia
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  8. Zsuzsanna Sandor
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  9. Sandor Szabo
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Correspondence to Sandor Szabo.

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Tolstanova, G., Deng, X., Ahluwalia, A. et al. Role of Dopamine and D2 Dopamine Receptor in the Pathogenesis of Inflammatory Bowel Disease. Dig Dis Sci 60, 2963–2975 (2015). https://doi.org/10.1007/s10620-015-3698-5

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