A review of melatonin in hepatic ischemia/reperfusion injury and clinical liver disease

Figures & data

Figure 1. The relationship between melatonin and endothelial dysfunction in hepatic IRI. Melatonin exerts hepatoprotective effects via inhibition of iNOS, stimulation of eNOS, and reduction of TNF-α and ET-1. Endothelial dysfunction leads to vascular stress and remodeling and to the expression of pro-inflammatory and pro-apoptotic genes, thus worsening hepatic IRI. eNOS = endothelial NO synthase; ET-1 = endothelin-1; iNOS = inducible NO synthase; IRI = ischemia/reperfusion injury; TNF-α = tumor necrosis factor α.

Figure 2. The involvement of mitochondria in apoptotic cell death and cellular necrosis. The overproduction of ROS by the mitochondria causes lipid peroxidation. Lipid peroxidation increases the permeability of the mitochondrial membrane. The increased membrane permeability ultimately leads to a loss of mitochondrial integrity that results in the release of cytochrome c into the cytoplasm, the subsequent activation of caspase activity, and the initiation of apoptotic cell death. ROS = reactive oxygen species.

Table I. The effects of melatonin on experimental models subjected to hepatic IRI.

Model	Effects of melatonin	Reference
Young and old Wistar and Zucker rats	Results showed an increase in both plasma transaminase as well as cytokines or oxidative stress and pro-apoptotic parameters. The elevation was higher in old and Zucker rats. Treatment with melatonin significantly reduced hepatic damage, being oral administration more effective	Hernández, 2011 (5)
Male Sprague-Dawley rats	Melatonin attenuated the levels of TLR3 and TLR4 protein expression, TRIF expression, TNF-α, IL-6, and iNOS protein and mRNA expression, and the phosphorylation of IRF3 and serum IFN-β; inhibited the release of HMGB1; suppressed the increase in MyD88 protein expression, ERK, JNK, and phosphorylated c-Jun; augmented the level of HO-1	Kang et al., 2011 (7)
Adult female Sprague-Dawley rats	Melatonin significantly improved animal survival and decreased transaminase levels, the indices for necrosis, liver damage, leukocyte infiltration, and iNOS expression. In parallel, the expression of IKK-α, JNK-1, and c-Jun decreased after melatonin. At the same time, melatonin reduced the expression of both PCNA and Ki67 in liver	Liang et al., 2009 (8)
Wistar albino rats	Melatonin and NAC have beneficial effects against the IRI and due to their synergistic effects, when administered in combination, may have a more pronounced protective effect on the liver	Zamzami et al., 1997 (37)
Male Sprague-Dawley rats	Melatonin restored the respiratory control index, ADP/O, state 3 respiration, dinitrophenol-induced uncoupled respiration, and mitochondrial structure; reduced the suppression of pH change and mitochondrial energy transfer and the decrease of mitochondrial glutathione peroxidase activity; attenuated mitochondrial lipid peroxidation	Okatani et al., 2003 (41)

ERK = extracellular signal-regulated kinase; HMGB1 = high-mobility group box 1; HO-1 = heme oxygenase-1; IFN-β = interferon β; IKK-α = IκB kinase α; IL-6 = interleukin 6; iNOS = inducible NO synthase; IRF3 = IFN regulatory factor 3; IRI = ischemia/reperfusion injury; JNK = c-Jun N-terminal kinase; MyD88 = myeloid differentiation factor 88; NAC = N-acetylcysteine; PCNA = proliferating cell nuclear antigen; TLR = toll-like receptor; TNF-α = tumor necrosis factor α; TRIF = toll-receptor-associated activator of interferon.

Figure 3. The downstream pathways of melatonin in hepatic IRI. Melatonin increases HO-1 and inhibits JNK. HO-1 inhibits JAK2/STAT1, TRIF, IFN-β, CXCL-10, and MyD88. Bicyclol, NAC, neutrophils, and repressed MyD88 cause attenuation of TLR4. TLR4 repression leads to the suppression of NF-κB. These changes result in hepatoprotection. CXCL-10 = C-X-C motif ligand 10; HO-1 = heme oxygenase 1; IRI = ischemia/reperfusion injury; JAK2 = Janus kinase 2; JNK = c-Jun N-terminal kinase; MyD88 = myeloid differentiation factor 88; NAC = N-acetylcysteine; NF-κB = nuclear factor κB; STAT1 = signal transducer and activator of transcription 1; TLR-4 = toll-like receptor 4; TRIF = toll-receptor-associated activator of interferon.

Table II. Clinical evidence supporting the protective effects of melatonin in liver diseases.

Disease	Melatonin in research	Reference
Hepatitis	In patients with drug-induced hepatitis, the incorporation of melaxen or epifamin into the treatment regimen was accompanied by a correction of the antioxidant status of the patients and provided a more pronounced antioxidant effect	Popov et al., 2011. (75)
	A statistically significant reduction was observed in GGT, triglycerides and pro-inflammatory cytokine levels in melatonin-treated and L-tryptophan-treated patients with steatohepatitis, suggesting that melatonin and tryptophan have a significant impact on the reduction in plasma levels of pro-inflammatory cytokines and may be useful in the treatment of patients with NASH	Cichoz-Lach et al., 2010. (81)
	Three months of treatment with melatonin significantly improved plasma liver enzymes in patients with NASH without causing any side effect	Gonciarz et al., 2010. (82)
	AST and GGT levels decreased significantly only in the melatonin-treated group, demonstrating the beneficial effect of melatonin on liver enzymes in patients with NASH	Gonciarz et al., 2012. (83)
Liver transplantation	The addition of melatonin and TMZ to IGL-1 solution improved steatotic liver graft preservation through AMPK activation, which reduced ER stress and increases autophagy	Zaouali et al., 2013. (80)
Liver cirrhosis and hepatic encephalopathy	Disturbances in serotonin and melatonin homeostasis observed in patients with liver cirrhosis may be associated with advanced encephalopathy	Chojnacki et al., 2012. (86)
	Elevated melatonin blood levels were observed in alcoholic cirrhotic patients both at night and day, which may have accounted for some of the clinical manifestations of hepatic encephalopathy (day-time sleepiness, fatigue)	Chojnacki et al., 2013. (87)
Liver cancer	In addition to a definite protective effect on liver damage caused by TACE, melatonin treatment enhanced the immunological activities of patients with inoperable advanced primary hepatocellular carcinoma. Melatonin also improved the effect of TACE by increasing the survival and resection rate after two-stage operation	Yan et al., 2002. (91)
	Melatonin-induced control or neoplastic cell growth was associated with a decline in VEGF secretion, suggesting that the pineal hormone may control tumor growth at least in part by acting as a natural anti-angiogenic molecule, leading to antagonism of angiogenesis-dependent cancer proliferation	Lissoni et al., 2001. (92)

AMPK = AMP-activated protein kinase; AST = aspartate transaminase; ER = endoplasmic reticulum; GGT = gamma-glutamyl transpeptidase; NASH = non-alcoholic steatohepatitis; TACE = transcatheter arterial chemoembolization; TMZ = temozolomide; VEGF = vascular endothelial growth factor.

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