Evaluation of Effect of Sertraline on Inflammatory Bowel Disease and its Chemopreventive Potential in Combination with 5-Fluorouracil in Colorectal Carcinoma in Mice

Abstract

1.1 INFLAMMATORY BOWEL DISEASE Aim and Objective: Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology which is characterized by chronic and spontaneously relapsing inflammation. The aim of present investigation was to study the anti-inflammatory effect of sertraline in acetic acid induced experimental colitis in BALB/c mice. Materials and Methods: All BALB/c mice of either sex were divided in six groups: Normal control (NC), Control treated with sertraline (CT-S), Control treated with prednisolone (CT-P), induced control (IC), Induced treated with sertraline (IT-S) and Induced treated with prednisolone (IT-P). The colitis was induced by intrarectal instillation of single dose of 0.1 ml 6 % acetic acid. Sertraline (10 mg/kg, p.o) and prednisolone (1.14 mg/kg, p.o) (standard) were given once a day from day 0 to day 10. Parameters like change in body weight, colon weight to length ratio and fecal occult blood test; macroscopic score like colon mucosal damage index (CMDI) and disease activity index (DAI); percentage protection of mast cell; serum biochemical markers like, lactate dehydrogenase (LDH), Gamma-glutamyl transferase (GGT) and C-reactive protein (CRP); oxidative stress parameters in colon homogenate like malondaldehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD); and histopathological evaluation of colon tissue were performed. Result: Intrarectal instillation of acetic acid resulted significant decreased body weight of animals, serum anti-oxidants (SOD and GSH) level and percentage mast cell protection. Treatment with sertraline resulted in significant increase in body weight of animals, serum anti-oxidants level and percentage mast cell protection. Moreover significant increased biochemical markers (LDH, GGT, CRP), colon mucosal damage index (CMDI) and disease activity index (DAI) were found in acetic acid induced groups. Whereas sertraline treated animals showed a significant reduction in biochemical markers (LDH, GGT, and CRP), colon mucosal damage index (CMDI) and disease activity index (DAI). Histological evaluation of colon tissue showed effective treatment with sertraline as compared to induced control group in terms of necrosis, hyperemia and infiltration of inflammatory cells. Conclusion: Result of the present study indicates that sertraline can protect acetic acidinduced colitis in mice and may be beneficial in patients with inflammatory bowel diseases. 1.2 COLORECTAL CARCINOMA Aim and Objective: Colorectal cancer (CRC) is the third leading cause of cancer-related death. It starts in the epithelial cells that line inside the colon and rectum. The present study was carried out to evaluate chemopreventive potential of Sertraline and its combination with 5-Fluorouracil in colorectal carcinoma in mice. Materials and Methods: Ninety six BALB/c mice of either sex were divided in eight groups: Normal control (NC), Control treated with sertraline (CT-S), Control treated with 5-fluorouracil (CT-FU), Control treated with combination of sertraline and 5-fluorouracil (CT-S+FU), Induced control (IC), Induced treated with sertraline (IT-S) and Induced treated with 5-fluorouracil (IT-FU) and Induced treated with combination of sertraline and 5-fluorouracil (IT-S+FU). Colorectal carcinoma was induced by administration of 1, 2- dimethyl hydrazine (DMH, 20 mg/kg, s.c) once a week for 14 weeks. After 14 weeks of induction, the treatment with sertraline (10 mg/kg, p.o), 5-fluorouracil (25 mg/kg, p.o) and their combination were started once a day for next 10 weeks. Parameters like change in body weight and fecal occult blood test; tumor assessments like tumor incidence, tumor multiplicity, tumor volume and tumor burden; cancer markers like Carcino Embryonic Antigen (CEA) and Cancer Antigen 19.9 (CA 19.9); biochemical markers in serum like LDH, GGT and CRP; oxidative stress parameters in colon homogenate like MDA, GSH and SOD; CNS parameters like despair swim test and tail suspension test; hematological parameters like Red Blood Cells (RBC) and White Blood Cells (WBC); histopathological evaluation of colon tissue for hyperplasia/neoplasia and/or carcinoma and finally quantification of Aberrant Crypt Foci (ACF) were performed. Results: Administration of DMH resulted significant decreased body weight and serum anti-oxidants (SOD and GSH) level. Treatment with sertraline, 5-fluorouracil and their combination caused significant increase in body weight and serum anti-oxidants level. A marked increase in tumor multiplicity, tumor incidence, tumor volume and tumor burden; CA 19.9; LDH, GGT and CRP were observed in DMH induced group whereas more reduction in values of these parameters were found in combination therapy as compared to 5-fluorouracil monotherapy. Moreover the significant decreased blood cell (WBC an RBC) and depressive behavior (immobility) in the DMH induced group was observed which was found to be more improved in combination therapy as compared to monotherapy. Histopathological evaluation of colon tissue of DHM induced group showed hyperplastic crypts and Squemous cell carcinoma whereas the combination treatment group showed more reduction in hyperplasia and no of ACF as compared to 5-fluorouracil alone treated group. Conclusion: Our present study has revealed that the combination of sertraline and 5-fluorouracil treatment may possess more predominant effect than 5-fluorouracil alone in the treatment of colorectal carcinoma.