| dc.description.abstract | Gastric ulcer and its treatment is a global problem, thus the search for a novel drug becomes a continuous one. Risperidone, though, anti-psychotic has been found to exhibit anti-ulcer activity, however, its mechanisms of action are yet to be fully elucidated. The study was designed to investigate the mechanisms underlying its anti-ulcer activity in rats. Three hundred and thirty-six male Wistar rats (180-210 g) were divided into 5 groups of 96, 48, 96, 64 and 32 rats respectively and treated orally for 21 days. Ninety-six of them were
divided into 3 sub-groups to be induced with ulcer using indomethacin, starvation and Water Immersion Restraint Stress (WIRS) methods. Each sub-group was pre-treated with distilled water (control) and risperidone (0.1, 0.3, 0.5 mg/kg). Forty-eight rats were further divided Into 6 groups; risperidone (0.5 mg/kg), indomethacin (40mg/kg), cyclooxygenase-1 inhibitor (SC-560, 40mg/kg), cyclooxygenase-2 inhibitor (celecoxib, 15 mg/kg), celecoxib + SC-560 and celecoxib + SC-560 risperidone. Gastric ulcers were scored using standard techniques. Ninety-six rats were divided into 3 sub-groups, with each group treated with distilled water and risperidone (1.1, 0.3, 0.5 mg/kg) and were assessed for Gastric Acid Secretion (GAS) induced by histamine, pentagastrin and carbachol using continuous perfusion techniques. Sixty-four rats were divided into 2 sub-groups and treated with distilled water and risperidone (0.1, 0.3, 0.5 mg/kg) for the assessment of Gastric Mucus Secretion (GMS) and Gastric Mucus Cell Counts (GMCC) using spectrophotometry and calibrated microscopy respectively. Thirty two rats divided into four treatment groups; distilled water and risperidone (0.1, 0.3, 0.5 mg/kg) were used for determination of malondialdehyde level by spectrophotometry. Histological studies on stomach tissues were done after staining with H&E and PAS stains using light microscope. Data were analysed using Student's t-test and ANOVA at p= 0.05.
Risperidone caused a significant dose-dependent reduction in gastric ulcer scores [0.1mg/kg (3.5±4.2), 0.3mg/kg (1.9±0.3), 0.5mg/kg (1.2±0.2)] compared with control (5.6±0.3) in WIRS., [0.1 mg/kg (4.0 ±0.3), 0.3mg/kg (2.3±0.2), 0.5mg/kg (1.8.±0.2)] compared with control
(6.1 ± 0.3) in starvation and [0.1 mg/kg (4.9±0.3), 0.3 mg/kg (2.0±0.2), 0.5 mg/kg (1.3±0.2)] compared with control (6.4±0.4) in indomethacin-induced ulcer models. Celecoxib in combination with SC-560 caused significant gastric damage with gastric ulcer score of 4.3±0.4, which was significantly reduced by risperidone (0.5 mg/kg; 1.6±0.2). Risperidone significantly inhibited GAS induced by histamine and pentagastrin but not GAS produced by carbachol. The GMS (mg/g tissue 10⁻²) increased significantly in the 0.1 mg/kg (1.1±0.1), 0.3mg/kg (1.3±0.1) and 0.5mg/kg (1.4±0.2) compared with the control (0.6±0.03). There was a dose-dependent increase in the GMCC (mm²) in risperidone-treated groups [0.1 mg/kg, 121.2±5.0), 0.3mg/kg (129±2.5) and 0.5mg/kg (129±3.8)] relative to the control (103.3±4.2). Malondialdehyde (nmonl/L 10⁹) level was significantly decreased by risperidone [0.1mg/kg (194.0±0.01), 0.3mg/kg (183.0± 0.01) and 0.5mg/kg (106.0± 0.01) compared to control group (257.0± 0.01). Histology revealed reduced mucosal epithelial and lamina propria damage in risperidone-treated groups compared with control.
Risperidone reduced gastric ulceration via mechanisms related to inhibition of gastric acid secretion mediated through histamine H₂ and gastrin receptors. Its anti-ulcer property may also be related to its antioxidant, gastroprotective and cyclooxygenase modulating activities. | en_US |
