Inhibition of carbon tetrachloride–mediated apoptosis and oxidative stress by melatonin in experimental liver fibrosis

Abstract

Melatonin, the principal secretory product of the pineal gland, functions as a potent antioxidant and free radical scavenger. Additionally, the antiapoptotic effect of melatonin has been observed both in vivo and in vitro. The aim of this experimental study was to investigate the protective effects of melatonin against carbon tetrachloride (CCl(4))-induced apoptosis and oxidative stress in rat liver. Twenty-four male Wistar rats were divided in three equal groups. Group I was used as control. Rats in group II were injected every other day with CCl(4) (0.5A mL/kg BW) for a month, whereas rats in group III were treated every other day with the same dose of CCl(4) plus melatonin (25A mg/kg BW). At the end of the experiment, all animals were killed by decapitation and the livers were rapidly removed. Some of the liver tissue specimens were used for determination of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. The remaining tissue specimens were processed for immunohistochemical assessment, and the percentage rates of apoptotic liver cells stained with immunoreactive Bax were determined. Chronic administration of CCl(4) significantly increased liver MDA contents, as an end product of lipid peroxidation, and also significantly decreased SOD and GSH-Px activities, emphasizing the generation of increased oxidative stress. Moreover, it caused an evident increase in apoptotic cells. Melatonin treatment significantly reduced MDA levels and elevated SOD and GSH-Px activities in rats received CCl(4) plus melatonin. Furthermore, apoptotic changes caused by CCl(4) were considerably decreased in these animals. The results of the present study indicate that melatonin treatment substantially prevents CCl(4)-induced apoptosis and oxidative damage in the liver. Thus, melatonin may serve as a drug for treating many clinical conditions that arise from inappropriate apoptosis.

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

“…Formation of fibrotic septa and increase in enzyme levels were impaired in animals treated with melatonin (5 and 10 mg/kg body weight), which is in line with previous reports on the effect of the pineal hormone in mice or rats with CCl 4 -induced fibrosis. [16][17][18][19][20][21][22] The critical step in the generation of liver fibrosis is the activation of HSCs resulting in a-SMA and collagen deposition. 28 The increased a-SMA expression in the livers of CCl 4 -treated mice was significantly diminished by melatonin administration, as indicated by immunohistochemical staining.…”

“…15 Using this toxinmediated model, it has been found that melatonin administration, at doses ranging from 2.5 to 20 mg/kg body weight, prevents liver histopathologic changes, reduces hepatic hydroxyproline content, inhibits oxidative stress and apoptosis, increases antioxidant enzyme levels, or reduces proinflammatory cytokine production, when administered intraperitoneally to rats or mice. [16][17][18][19][20][21][22] However, in these in vivo studies, effects of melatonin on the activation of HSCs and changes in the expression of fibrogenic factors or molecules involved in ECM degradation have not been tested. Moreover, because melatonin was always given before or in parallel to CCl 4 administration, only a preventive effect before the onset of liver toxicity was demonstrated.…”

The effects of Juglans regia L. (walnut) extract on certain biochemical paramaters and in the prevention of tissue damage in brain, kidney, and liver in CCl4 applied Wistar rats

“…CCl 4 is a substance that is used widely to generate experimental liver cirrhosis and its pro-oxidant activity is well known [9,10]. CCl 4 is metabolized to haloalkane free-radicals (CCl3 and CCl3O2 • ) by mixed function cytochrome oxidase complex that uses (NADPH)-cytochrome P450 electron transport chain in the hepatic smooth endoplasmic reticulum [11]. These substances generated cause hepatotoxic CCl 4 , initiating lipid peroxidation in the membranes [12,13].…”

Effective melatonin protection of burn-induced hepatic disorders in rats

“…As scavenger of both reactive oxygen species (ROS) and reactive nitrogen species (RNS), melatonin protects DNA, lipids and proteins against oxidative damage. [7] Melatonin has a potent protective effect on liver injury induced by ischemia/reperfusion and toxins such as carbon tetrachloride, alcohol and cyclosporine A [8][9][10]. Previous studies showed that melatonin restricts oxidative damage in the liver, as well as production of acute-phase hepatic proteins and plasma transaminase as indicators of hepatic injury and functional disorders after burns [11,12].…”