Melatonin administration prevents lipopolysaccharide-induced oxidative damage in phenobarbital-treated animals.
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 Nw-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Sewerynek
E
E
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio 78284, USA.
Abe
M
M
Reiter
R J
RJ
Barlow-Walden
L R
LR
Chen
L
L
McCabe
T J
TJ
Roman
L J
LJ
Diaz-Lopez
B
B
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004926:Escherichia coli; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D019803:Glutathione Disulfide; D005979:Glutathione Peroxidase / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008070:Lipopolysaccharides; D009569:Nitric Oxide; D001120:Arginine; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D009251:NADPH-Ferrihemoprotein Reductase; D005978:Glutathione; D008550:Melatonin; D019803:Glutathione Disulfide; D019331:NG-Nitroarginine Methyl Ester; D010634:Phenobarbital