Protective Effect of Agomelatine against Acetic Acid-Induced Ulcerative Colitis in Male Albino Rats

Abstract

Background:Ulcerative colitis (UC) is a form of idiopathic inflammatory bowel disease (IBD) with repeated and widespread mucosal inflammation of the rectum and colon. It is characterized by cycles of acute inflammation, ulceration and colonic mucosal bleeding. It is listed as one of the modern refractory diseases by the World Health Organization (WHO).Agomelatine which is atypical antidepressant with a unique receptor profile and works as a melatonin receptor (MT₁ and MT₂) agonist and a 5-HT_2C receptor antagonist.

Aim of study:This study aimed to evaluate the possible protective effects of agomelatineversus mesalazine on experimentally induced UC and to explore the underlying mechanisms of its anti-inflammatory and antioxidant effects in UC.

Materials and Methods:Forty-eight male albino rats weighting 180-200 gm/rat were randomly allocated to six groups(8 rats for each group) as follows: Group Ⅰ {Control group}, Group II{Vehicle-Pretreated group}, Group III {Acetic Acid (AA)-group}, Group IV{Small dose Agomelatine-Pretreated UC group (Ago-10)}, Group V{Large dose Agomelatine-Pretreated UC group (Ago-40)}, and Group VI {Mesalazine (Mes)-Pretreated UC group}.The drugs were administrated orally by oral gavage for 14 days before induction of UC and continued for 2 days after induction. Ulcerative colitis was induced on the 15^th day by instillation of 4% acetic acid rectally in groups (III, IV, V and VI). After 48 hours, animals were sacrificed and colon samples were collected.  To estimate the severity of AA-induced UC and the effect of agomelatine and mesalazine, the following parameters had been measured: disease activity index (DAI), colon weight/body weight (CW/BW) ratio,ulcer index (UI),macroscopic scoring, microscopic scoring, Sirtuin1 (SIRT1), p38 mitogen-activated protein kinase  (p38 MAPK), pro-inflammatory markers (tumor necrosis factor {TNF}-α&interleukin-1 beta {IL-1ꞵ}) and oxidative stress parameters (nuclear factor-erythroid-related factor 2{Nrf-2}, heme oxygenase-1 {HO-1} and superoxide dismutase {SOD}).

Results:In the AA-group, theDAI, CW/BW ratio,UI, macroscopic scoring and microscopic scoring were significantlyincreased, SIRT1 level was significantly decreased and p38 MAPK was significantly increased when compared to the control groups.The pro-inflammatory cytokines (TNF-α& IL-1ꞵ) were significantly increased and the oxidative stress parameters (Nrf2, HO-1and SOD) were significantly decreased as compared to the control groups. Pretreatment with agomelatine significantly reduced the DAI, CW/BW ratio, UI, macroscopic scoring and microscopic scoring.Also, SIRT1 level was significantly increased and p38 MAPK was significantly decreased in a dose-dependent manner when compared to the AA-group.The pro-inflammatory cytokines (TNF-α& IL-1ꞵ) were significantly decreased while the oxidative stress parameters (Nrf2, HO-1and SOD) were significantly increased as compared to the AA-group in a dose-dependent manner. However, better results were observed with a dose of 40 mg/kg/day which was insignificantly different from that of mesalazine 100 mg/kg pretreated group as a standard therapy.

Conclusion:It can be concluded that agomelatine has a dose dependent protective effects against AA- induced colitis in male albino rats which was insignificantly different from that obtained by mesalazine the standard therapy.  Agomelatine may exert these protective effects through MT receptors-dependent mechanisms which could explain the anti-inflammatory and antioxidant effects of agomelatine in experimentally induced UC.