Ulcerative colitis refers to destruction of mucosal layer of distal colon and rectum. Exact mechanism for pathophysiology is still unclear but inflammation and oxidative stress may play a caustic role. Neutrophil and monocyte infiltration results in free radical generation which damages intestinal mucosa. Many treatments as steroids are used to reduce inflammation but cannot cause remission. Carvedilol is a third-generation nonselective β-blocker which possesses anti-oxidant, anti-inflammatory properties and can reduce gastric ulceration. Celecoxib is a selective cyclooxygenase -2 (COX-2) inhibitor which decrease risk of gastrointestinal bleeding. The current study was designed to compare the efficacy of carvedilol and celecoxib to prednisolone in acetic acid-induced ulcerative colitis model. A total of 40 adult male albino rats were randomly divided into five groups: Control group: Rats received 2 ml of saline transrectal. Acetic acid (AA) group: Rats were transrectal injected with 2ml acetic acid. Prednisolone +AA group: Rats were pre-treated with prednisolone in a dose 4mg/kg /day. Carvedilol +AA group: Rats were pre-treated with carvedilol in a dose 30 mg/kg/day. Celecoxib +AA group: Rats were pre-treated with celecoxib in a dose 5mg/kg/day. All drugs were given orally for 7 days. At end of experiment, distal colon was removed, one part of specimen was preserved in 10% formalin for histological examination and other part was homogenized for evaluation of tumor necrosis factor alpha (TNF-α), reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and mitogen-activated protein kinase ( p38 MAPK). Data of present study revealed that treatment of rats with carvedilol or celecoxib before induction of colitis significantly reduced levels of TNF-α, MDA, NO and mRNA level of p38 MAPK while both drugs increased GSH level. Protective effects of Carvedilol and celecoxib are due to anti-inflammatory, anti-oxidant effects and ability to decrease synthesis of MAPK which reduce cytokines signaling in epithelial cells of gut mucosa.
Deferasirox belongs to a new is a bishydroxyphenyltriazoles iron chelator used for treatment of chronic iron overload. The use of Deferasirox is associated with hepatotoxicity. Silymarin is a benzo gamma-pyrones flavonoid which affords hepatoprotection and preserves hepatocyte membranes by its antioxidant effect. Curcumin is a poly-phenol compound naturally concentrated in the herb Curcuma longa. The present study was conducted to evaluate and compare the hepatoprotective effects of both silymarin and curcumin against deferasirox-induced hepatotoxicity in rats and to explore the potential mechanisms account for their hepatoprotective effects. The present study was carried out using 32 male wistar randomly assigned into 4 groups (8 rats each) as follows; Group1: served as normal control group in which rats received distilled water (0.5ml per rat) by oral gavage. Group II (Deferasirox group) in which hepatotoxicity was induced by oral administration of deferasirox in a dose of 100 mg/kg once daily for 4 weeks dissolved in distilled water for a concentration of 35mg/ml. Group III (deferasirox+ curcumin) in which rats received curcumin in a dose of 100 mg/kg daily dose by oral gavage for 4 weeks suspended in distilled water for a concentration of 35 mg/ml one hour before administration of deferasirox. Group IV (deferasirox+ silymarin) in which rats received silymarin in dose of 7.56 mg/kg once daily by oral gavage for 4 weeks suspended in distilled water for a concentration of 2.7mg/ml one hour before administration of deferasirox. At the end of the treatment period, all rats were sacrificed by cervical dislocation, blood samples were collected for measurement of ALT, AST, ALP and total bilirubin. Liver samples were used for measurement of MDA, GSH and IL-6. Histopathological and immunohistochemistry were also done. The present data revealed that rats pretreated with curcumin or silymarin exhibited significant reduction in ALT, AST, ALP, total bilirubin, IL-6 and MDA levels with significant elevation of GSH level compared to deferasirox group. In-between group comparison revealed that there was a more significant reduction in ALT, AST, ALP, total bilirubin, IL-6 and MDA in group IV compared to group III. In conclusion, both curcumin and silymarin represent natural protective agents against Deferasirox-induced hepatotoxicity due to their antioxidant and anti-inflammatory effects.
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