Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA211

Poster Communications

Role of central dopaminergic system and D2-dopamine receptor in the pathogenesis of experimental ulcerative colitis in rats

K. Nesteruk1, A. Pryisiazhniuk1, T. Dovbynchuk1, B. Kopiak2, T. Chervinska1, S. Talanov2, G. Tolstanova1

1. ESC "Institute of biology" Taras Shevchenko National University of Kiev, Kiev, Ukraine. 2. Institute of Physiology named after O.O.Bogomolets NAS of Ukraine, Kiev, Ukraine.

Ulcerative colitis (UC) is a chronic inflammatory disease with poorly understood etiology. Others and we showed disturbance of dopaminergic system in UC pathogenesis. Treatment with D2 receptor (D2R) agonist, which are able to cross blood brain barrier, ameliorated clinical and morphological signs of experimental UC (1). In present study, we tested the hypothesis on the protective role of central vs peripheral dopaminergic system in UC pathogenesis. Study was done on male Wistar rats (200-250g, n=35). The unilateral nigrostriatal lesion was caused by intranigral injection of 6-hydroxydopamine (6-OHDA). The area of destroyed central dopaminergic neurons were estimated by apomorphine test: <180 turns/30 min - 44% of destroyed central dopaminergic neurons; >180 turns/30 min - 95% (2). Experimental UC was induced by 0.1 ml of 6% iodoacetamide enema. Level of colonic endothelial permeability by Evans blue extravasation were measured after treatment with central quinpirole D2R agonist (10 mg/kg, per os) and domperidone, peripheral D2R antagonist (20 mg/kg, per os). These procedures were done under Nembutal anesthesia (50 mg/kg, i.p.). Disease activity index was calculated by estimation of the lethargy, diarrhea, and weight loss. The myeloperoxidase activity, proteins level by Western blots were detected in colonic mucosa. Rats were euthanized by CO2 inhalation followed by cervical dislocation. The statistical significance was determined by the Student's t-test. The disturbance of central dopaminergic neurons by 6-OHDA administration increased Disease activity index 1.5-fold (p<0.05); the ratio of colon wet weight/100g body weight 2-fold (p<0.05); and myeloperoxidase activity 2.5-fold (p<0.05) in rats with UC vs sham rats with UC. These effects positively correlated with area of destroyed central dopaminergic neurons. Basal level of colonic endothelial permeability was equal in sham and 6-OHDA rats. Development of iodoacetamide-induced inflammation was associated with 1.4-fold (p<0.05). higher levels of colonic endothelial permeability in 6-OHDA vs sham rats. It was accompanied by upregualtion of phosphorylated caveolin-1 (Tyr 14) (1.4-folds) and ICAM-1 (5.5-folds) levels in colonic mucosa vs sham rats. There was no changes in level of VEGF. Quinpirole decreased colonic endothelial permeability in 1.7-fold (p<0.05) in rats with UC. Treatment with domperidone didn't affect quinpirole-induced changes in colonic endothelial permeability. We showed for the first time that damage of central dopaminergic neurons aggravated severity of UC in rats. These effects at least partially dependent on increased colonic endothelial permeability and adhesive potential of endothelial cells via dysregulation of central D2R activity.

Where applicable, experiments conform with Society ethical requirements