Protective effect of low dose of melatonin against cholestatic oxidative stress after common bile duct ligation in rats.
OBJECTIVE
To investigate the role of oxidative injury and the effect of exogenous melatonin administration on liver damage induced by bile duct ligation (BDL), and second, to evaluate the role of nitric oxide (NO), a free oxygen radical, in oxidative injury.


METHODS
Thirty-two Sprague-Dawley rats were assigned to four groups: sham operation (SO), BDL, BDL+melatonin, and BDL+vehicle. Cholestasis was achieved by double ligature of the common bile duct. Melatonin was injected intraperitoneally 500 microg/(kg.d) for 8 d. Hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides, measured as malondialdehyde (MDA), and reduced GSH. Total nitrite (NOX) concentrations were determined in hepatic homogenates. Histopathological examination was performed using a histological scoring system.


RESULTS
The histopathological changes including portal inflammation, necrosis, apoptosis, focal inflammation and fibrosis were severe in the BDL and BDL+vehicle groups. There were numerous large areas of coagulation necrosis. Histological Activity Index scores of these groups were significantly higher than that of the SO group. Treatment with melatonin reduced these alterations significantly. The degree of necro-inflammation and fibrosis showed significant difference between the BDL and BDL+melatonin groups. BDL was accompanied by a significant increase in MDA and NOX, and a significant decrease in GSH levels. Mean+/-SE values of MDA, GSH and NOX levels of SO group were 147.47+/-6.69, 0.88+/-0.33 micromol/g and 180.70+/-6.58 nm/g, respectively. The values of BDL group were 200.14+/-21.30, 0.65+/-0.02 micromol/g, and 400.46+/-48.89 nm/g, respectively, whereas the values of BDL+melatonin group were 115.93+/-6.8, 0.74+/-0.02 micromol/g, and 290.38+/-32.32 nm/g, respectively. Melatonin treatment was associated with a significant recovery of MDA, GSH and NOX levels.


CONCLUSIONS
We have concluded that oxidative stress is associated with the pathogenesis of cholestatic liver damage and NO contributes to oxidative damage. Melatonin, even at low dose, is an efficient agent in reducing negative parameters of cholestasis.
Esrefoglu
Mukaddes
M
Department of Histology and Embryology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey. drmukaddes@hotmail.com
Gül
Mehmet
M
Emre
Memet-Hanifi
MH
Polat
Alaattin
A
Selimoglu
Mukadder-Ayse
MA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001651:Cholestasis, Extrahepatic; D003135:Common Bile Duct / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D008026:Ligation; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
D000975:Antioxidants; D008550:Melatonin