Melatonin administration prevents lipopolysaccharide‐induced oxidative damage in phenobarbital‐treated animals

Abstract

The protective effect of melatonin on lipopolysaccharide (LPS)‐induced oxidative damage in phenobarbital‐treated rats was measured using the following parameters: changes in total glutathione (tGSH) concentration, levels of oxidized glutathione (GSSG), the activity of the antioxidant enzyme glutathione peroxidase (GSH‐PX) in both brain and liver, and the content of cytochrome P450 reductase in liver. Melatonin was injected intraperitoneally (ip, 4mg/kg BW) every hour for 4 h after LPS administration; control animals received 4 injections of diluent. LPS was given (ip, 4 mg/kg) 6 h before the animals were killed. Prior to the LPS injection, animals were pretreated with phenobarbital (PB), a stimulator of cytochrome P450 reductase, at a dose 80 mg/kg BW ip for 3 consecutive days. One group of animals received LPS together with N^w‐nitro‐L‐arginine methyl ester (L‐NAME), a blocker of nitric oxide synthase (NOS) (for 4 days given in drinking water at a concentration of 50 mM). In liver, PB, in all groups, increased significantly both the concentration of tGSH and the activity of GSH‐PX. When the animals were injected with LPS the levels of tGSH and GSSG were significantly higher compared with other groups while melatonin and L‐NAME significantly enhanced tGSH when compared with that in the LPS‐treated rats. Melatonin alone reduced GSSG levels and enhanced the activity of GSH‐PX in LPS‐treated animals. Additionally, LPS diminished the content of cytochrome P450 reductase with this effect being largely prevented by L‐NAME administration. Melatonin did not change the content of P450 either in PB‐ or LPS‐treated animals. In brain, melatonin and L‐NAME increased both tGSH levels and the activity of GSH‐PX in LPS‐treated animals. The results suggest that melatonin protects against LPS‐induced oxidative toxicity in PB‐treated animals in both liver and brain, and the findings are consistent with previously published observations related to the antioxidant activity of the pineal hormone.