Melatonin reduces dimethylnitrosamine‐induced liver fibrosis in rats

Abstract

Increased deposition of the extracellular matrix components, particularly collagen, is a central phenomenon in liver fibrosis. Stellate cells, the central mediators in the pathogenesis of fibrosis are activated by free radicals, and synthesize collagen. Melatonin is a potent physiological scavenger of hydroxyl radicals. Melatonin has also been shown to be involved in the inhibitory regulation of collagen content in tissues. At present, no effective treatment of liver fibrosis is available for clinical use. We aimed to test the effects of melatonin on dimethylnitrosamine (DMN)-induced liver damage in rats. Wistar albino rats were injected with DMN intraperitoneally. Following a single dose of 40 mg/kg DMN, either saline (DMN) or 100 mg/kg daily melatonin was administered for 14 days. In other rats, physiologic saline or melatonin were injected for 14 days, following a single injection of saline as control. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examination. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH) and superoxide dismutase (SOD) levels were evaluated in blood and tissue homogenates. DMN caused hepatic fibrotic changes, whereas melatonin suppressed these changes in five of 14 rats (P < 0.05). DMN administration resulted in increased hydroxyproline and MDA levels, and decreased GSH and SOD levels, whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin functions as a potent fibrosuppressant and antioxidant, and may be a therapeutic choice.

Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats

“…Cunnane et al [31] demonstrated that primary biliary cirrhosis is related with melatonin deficiency in pinealectomized rats. Tahan et al [12] reported that daily melatonin injection at pharmacological doses is effective against liver damage in a rat liver fibrosis model induced by a 14-d dimethylnitrosamine regimen. In the present study, liver injury was assessed with histological and biochemical parameters.…”

“…Both in vitro and in vivo experiments have shown that melatonin can protect cells, tissues, and organs against oxidative damage induced by a variety of free-radical-generating agents and processes, such as safrole, lipopolysaccharide (LPS), carbon tetrachloride (CCl 4 ), ischemia-reperfusion, amyloid-protein, and ionizing radiation [10][11][12] . In addition, melatonin also has an indirect antioxidant effect by enhancing the levels of potential antioxidants such as glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione (GSH) [10][11][12] .…”

“…Both in vitro and in vivo experiments have shown that melatonin can protect cells, tissues, and organs against oxidative damage induced by a variety of free-radical-generating agents and processes, such as safrole, lipopolysaccharide (LPS), carbon tetrachloride (CCl 4 ), ischemia-reperfusion, amyloid-protein, and ionizing radiation [10][11][12] . In addition, melatonin also has an indirect antioxidant effect by enhancing the levels of potential antioxidants such as glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione (GSH) [10][11][12] . Recent studies showed that melatonin exerts its cytoprotective effects in various experimental models of acute liver injury and reduces fibroblast proliferation and collagen synthesis [12,13] , indicating that melatonin may have therapeutic effects on acute and chronic liver injury, through its antioxidant action.…”

“…In addition, melatonin also has an indirect antioxidant effect by enhancing the levels of potential antioxidants such as glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione (GSH) [10][11][12] . Recent studies showed that melatonin exerts its cytoprotective effects in various experimental models of acute liver injury and reduces fibroblast proliferation and collagen synthesis [12,13] , indicating that melatonin may have therapeutic effects on acute and chronic liver injury, through its antioxidant action.…”

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

“…Melatonin is a versatile molecule endowed with an abrogated activation of HSCs induced by reactive oxygen species in vitro, 10 and different studies have shown that the pineal hormone prevents liver damage in rats with fibrosis induced by bile duct ligation, 11 dimethylnitrosamine, 12 or thioacetamide. 13 The most commonly used approach to cause experimental liver fibrosis is the periodic administration of carbon tetrachloride (CCl 4 ) in mice or rats.…”