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The protective in vivo effects of melatonin or pinoline on carbon tetrachloride (CCl4)-induced oxidative damage were investigated in liver of rats and compared to rats injected only with CCl4 (5 mL/kg body weight). Hepatic cell membrane fluidity, monitored using fluorescence spectroscopy, exhibited a significant decrease in animals exposed to CCl4 compared to control rats. Increases in lipid and protein oxidation, as assessed by concentrations of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA), and protein carbonylation, respectively, were also seen in hepatic homogenates of animals exposed to CCl4. The administration of melatonin (10 mg/kg body weight) or pinoline injected 30 min before and 1 hr after CCl4, fully prevented membrane rigidity and protein oxidation. However, treatment with melatonin was more effective in terms of reducing lipid peroxidation than pinoline, as the increases in MDA+4-HDA levels because of CCl4 were reduced by 93.4% and 34.4% for melatonin or pinoline, respectively. Livers from CCl4-injected rats showed several histopathological alterations; above all, there were signs of necrosis and ballooning degeneration. The concurrent administration of melatonin or pinoline reduced the severity of these morphological changes. On the basis of the biochemical and histopathological findings, we conclude that both melatonin and pinoline were highly effective in protecting the liver against oxidative damage and membrane rigidity because of CCl4. Therefore, these indoles may be useful as cotreatments for patients with hepatic intoxication induced by CCl4.