Protective Effect of Melatonin on Carbon Tetrachloride - induced Hepatic Fibrogenesis in Rats | ||
| Bulletin of Egyptian Society for Physiological Sciences | ||
| Article 15, Volume 30, Issue 1, December 2010, Pages 233-254 PDF (270.94 K) | ||
| Document Type: Original Article | ||
| DOI: 10.21608/besps.2010.36176 | ||
| Author | ||
| Mona El-Karn* | ||
| Medical Physiology Department, Faculty of Medicine, Assiut University | ||
| Abstract | ||
| Background: Liver cirrhosis is a critical stage of chronic liver diseases that can produce liver failure, portal hypertension and hepatic carcinoma. Sustained oxidative stress plays a key role in cell damage and fibrosis induced during liver cirrhosis. Aim of the work: The aim of the present study was to examine the potential protective effect of exogenous melatonin co-treatment on liver tissue injury and oxidative stress processes during induction of early phase of liver fibrosis by carbon tetrachloride (CCl4) injection in rats. Methods: Hepatic fibrogenesis model was induced in this study by subcutaneous injection of rats by carbon tetrachloride (CCl4). Eighteen adult, female albino rats were randomly divided into 3 groups (n = 6): control group (group I), carbon tetrachloride treated group (group II) and CCl4 + melatonin cotreated group (group III). Rats in CCl4 treated group were injected subcutaneously with sterile CCl4 (2 ml/kg of body weight) in a ratio of 1:1 with olive oil twice a week for 8 weeks. Rats of group III (melatonin co-treated group) were injected with CCl4 in the same manner as in group II and received intraperitoneal melatonin injection in a dose of 20 mg/kg twice a week for 8 weeks, starting from the beginning of CCl4 injection. Rats in normal control group were injected subcutaneously with olive oil at the same dose and frequency as those in CCl4 treated group. At the end of the experiment, rats were sacrificed, blood samples were collected for biochemical assay. Liver from each animal was removed for histopathological examination. Measurement of oxidative stress markers in serum was done by chemical estimation of serum levels of free radicals: lipid peroxides (LPO) and nitric oxide (NO). Antioxidant enzymes were estimated by chemical measurement of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in the serum. Liver injury was assessed by evaluation of serum levels of liver enzymes (alanine aminotransferase (ALT), and aspartate aminotransferase (AST)). Determination of development of early phase of hepatic fibrogenesis was done by chemical measurement of serum level of hyaluronic acid (HA) using enzyme immunoassay (ELISA), and by histopathological examinations of hepatic tissues to detect early fibrotic changes as well as other histological damage of hepatic tissue caused by CCl4 injection with or without melatonin administration. Results: Results of the present study showed that CCl4 treatment to rats of group II caused highly significant increase in serum levels of oxidative stress markers (lipid peroxides and nitric oxide), decrease in serum levels of antioxidant markers (glutathione peroxidase and superoxide dismutase), increase of serum levels of hepatic enzymes (ALT and AST) as well as increased serum level of hyaluronic acid (HA) 8 weeks after CCl4 injections when compared with control group. Melatonin co-treatment to animals of group III caused significant reduction in serum levels of lipid peroxides (LPS) and nitric oxide (NO), significant increase in plasma levels of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), significant reduction in serum levels of liver enzymes (ALT and AST) as well as significant decrease in serum level of hyaluronic acid (HA) 8 weeks after CCl4 injections when compared with group II. Histopathological study of liver tissue of animals of CCl4 treated group showed various manifestation of hepatic cell damage and early phase of fibrogenesis as necrosis, degeneration, collagen deposition and few fibrous threads extending into the hepatic lobules. Histopathological study of hepatic tissue of melatonin co-treated group showed that melatonin caused marked amelioration of histological manifestations of hepatic cell degeneration and absence of any sign of fibrogenesis with nearly normalization of the histological appearance of the hepatic tissue. Compared with CCl4 treated group (group II), histological appearance of hepatic tissue of rats in melatonin co-treated group (group III) showed significant improvement. Conclusion: Results of this study suggest that melatonin has a substantial hepatoprotective effect in a rat hepatic fibrosis model induced by an 8- weeks’ CCl4 regimen. The protective effect of melatonin may be due to both its direct radical scavenging properties and indirect effect as a regulator of antioxidant systems. Therefore, the study proposes that melatonin may be a valuable drug for inhibition of unwanted fibrosis in patients exposed to different hepatotoxic agents. | ||
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