Melatonin Prevents Oxidative Stress and Hepatocyte Cell Death Induced by Experimental Cholestasis

Abstract

The induction of oxidative stress precedes liver injury during experimental obstructive jaundice (OJ). In this sense, different evidences suggest that melatonin (MEL), as antioxidant, may be useful in the protection against apoptosis and necrosis during experimental cholestasis. In addition, we will also assess if MEL-dependent protection is related to a recovery of antioxidant status disturbances induced by OJ. Cholestasis was achieved by double ligature and sectioning of the principal bile duct. MEL was injected intraperitoneally (500 microg/kg/day). Lipid peroxidation was evaluated by the measurement of malondialdehyde (MDA) content in liver. Different parameters related to antioxidant status, such as reduced glutathione (GSH), glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were determined in liver. Liver injury was assessed by alanine amino-transferase (ALT) in serum, histological examination, DNA fragmentation and TUNEL assay. The activation of perisinusoidal stellate cells was evaluated by immunohistochemical measurement of alpha-smooth muscle actin in liver sections. The induction of OJ increased all the parameters related to apoptosis and necrosis in liver. The induction of liver injury was associated with stellate cell activation, as well as an increase in MDA (p < 0.0001) and a reduction in GSH, GPx, catalase and SOD content (p < 0.0001) in liver. MEL reduced hepatic apoptosis and necrosis (p < 0.004) with a significant improvement in all oxidative stress markers. In conclusion, our results showed that MEL recovered the antioxidant status and reduced apoptosis and necrosis induced by experimental cholestasis.

Effects of beta-glucan on hepatic damage caused by obstructive jaundice

“…[21] TS'de MDA düzeyinin arttığı çeşitli çalışmalarla ortaya konulmuştur. [18,[22][23][24][25][26] LPO'da benzer şekilde hücre-sel hasara işaret eder. Beta glukanın sepsis, yanık gibi durumlarda ortaya çıkan karaciğer hasarını ve MDA seviyesini azalttığını bildiren yayınlar vardır.…”

“…TS'de, GSH'nin azaldığı birçok çalışmada gösterilmiştir. [22][23][24][25][26] Şener ve arkadaşlarının [29] çalışmasında, kronik nikotin uygulamasının etkilediği böbrek ve mesanede, doku GSH seviyelerinin düştüğü ve beta glukan verilmesinin doku GSH seviyelerini anlamlı olarak arttığı tespit edilmiştir. Toklu ve arkadaşlarının [30] çalış-masında, beta glukanın asetaminofen kaynaklı karaciğer toksisitesinde GSH düzeyini arttırdığı ve karaci- ğer hasarını azalttığı bildirilmiştir.…”

Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats

“…It has been found that melatonin has a higher antioxidant efficiency than vitamin E and GSH, which are known as powerful antioxidants [10] . The antioxidant properties of melatonin prevent acute liver injury induced by ischemiareperfusion [23] , irradiation [24] , bile duct ligation [25][26][27] , and toxins [18,28,29] . Several lines of evidence suggest that melatonin plays an important role in regulation of collagen levels and inhibition of collagen accumulation.…”

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

“…2 Oxidative stress has an important role in hepatocyte cell death and hepatocellular injury during experimental induced cholestasis. 3 Actually, bile acids have been reported to stimulate the generation of reactive oxygen species in hepatocytes and liver mitochondria by their interference with mitochondrial electron transport chain. [4][5][6] Contrary to oxidative stress, the role of nitrosative stress in cholestatic liver diseases has received much less attention.…”