Evaluation of Central and Peripheral Effects of Doxepin on Acetic Acid-Induced Colitis in Rat and the Involved Mechanisms

Abstract

Anti-colitis effect of antidepressants has been demonstrated recently. Doxepin, a tricyclic antidepressant drug (TCA), with potent H-1, H-2, alpha(1) adrenergic and muscarinic receptor blocking effects could be a good candidate for investigation for its anti-colitis activity. Moreover high prevalence of depression in patients who suffer from IBD (inflammatory bowel disease), defends this idea that adjuvant therapy with an antidepressant drug which has anti-inflammatory effect, may exert favorable effects in the control of the disease. In this study colitis was induced by acetic acid instillation into rat's colon. Doxepin was injected by intraperitoneal (10, 20, 40 mg/kg, twice daily, i.p.) or intracerebroventricular (50 and 100 microgram/rat, i.c.v.) routes to separate the mechanisms are absolutely exerted centrally or mediated both centrally and peripherally prior to induction of colitis. Dexamethasone (2 mg/kg/day, i.p.) was used as reference drug. All the treatments continued for three successive days. The effectiveness of drug was evaluated by determination of cytokines (TNF alpha, IL6 and IL1 beta) and myeloperoxidase (MPO) activity as well as macroscopic scores and histopathological parameters. Doxepin after i.p. administration was effective to reduce colitis severity through reduction in the macroscopic and microscopic colonic parameters, MPO activity and cytokines levels. Intracerebroventricular administration of the drug in contrast, did not show any significant protective effect suggesting no important central mechanisms for anti-colitis activity of doxepin. Doxepin as an ancient antidepressive drug has anti-colitis and anti-inflammatory properties which are mainly exerted peripherally so it could be introduced as a good candidate for depressed people who suffered from IBD disorders.