Multiple protective effects of melatonin against maternal cholestasis‐induced oxidative stress and apoptosis in the rat fetal liver–placenta–maternal liver trio

Abstract

Maternal cholestasis is usually a benign condition for the mother but induces profound placental damage and may be lethal for the fetus. The aim of this study was to investigate the protective effects in rat maternal and fetal livers as also the placenta of melatonin or silymarin against the oxidative stress and apoptosis induced by maternal obstructive cholestasis during the last third of pregnancy (OCP). Melatonin or silymarin administration (i.e. 5 mg/100 g bw/day after ligation of the maternal common bile duct on day 14 of pregnancy) reduced OCP-induced lipid peroxidation, and prevented decreases in total glutathione levels. However, the protective effect on OCP-induced impairment in the GSH/GSSG ratio was mild in the placenta and fetal liver, while absent in maternal liver. Melatonin or silymarin also reduced OCP-induced signs of apoptosis (increased caspase-3 activity and Bax-alpha upregulation) in all the organs assayed. Moreover, melatonin (but not silymarin) upregulated several proteins involved in the cellular protection against the oxidative stress in rats with OCP. These included, biliverdin-IX alpha reductase and the sodium-dependent vitamin C transport proteins SVCT1 and SVCT2, whose expression levels were enhanced in maternal and fetal liver by melatonin treatment. In contrast, in placenta only biliverdin-IX alpha reductase and SVCT2 were upregulated. These results indicate that whereas the treatment of cholestatic pregnant rats with melatonin or silymarin affords a direct protective antioxidant activity, only melatonin has dual beneficial effects against OCP-induced oxidative challenge in that it stimulates the expression of some components of the endogenous cellular antioxidant defense.

Nitric oxide mimics transcriptional and post-translational regulation during α-Tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes

“…This The increase of MTP and ROS production was related to induction of cell injury in GCDCA-treated hepatocytes [7,8]. The cytoprotective properties of different agents was related to the reduction of oxidative stress and cell death in bile acid-induced cytotoxicity [7,[34][35][36][37]. a-Tocopherol reduces oxidant injury induced by bile acids in cultured hepatocytes [14,15] and in experimental models of cholestasis [38,39].…”

Melatonin enhances antioxidant action of α-tocopherol and ascorbate against NADPH- and iron-dependent lipid peroxidation in human placental mitochondria

“…Using of melatonin in preeclampsia has been proposed earlier by Okatani et al [28] and Tamura et al [44]. Furthermore, many reports have shown beneficial influence of melatonin on pregnancy [29,[45][46][47]; and according to our knowledge up to now, there is no reports about any important side effects of melatonin treatment. Hence, the results obtain here and data presented by others allow us to assume that melatonin combined with ascorbate and a-tocopherol can be useful for preventing preeclampsia and other free radical linked diseases of pregnancy.…”

Excretion of biliary compounds during intrauterine life

“…The transport of biliverdin from the trophoblast toward the mother is very poor and/or that placental biotransformation of biliverdin into bilirubin is very efficient. Part of the endogenous biliverdin produced by the fetus could be transformed into bilirubin by the fetal liver prior to being taken up by the placenta, because the expression of BVRα in fetal liver is even higher than in rat placenta [100] .…”

“…Sub-toxic bilirubin concentrations have direct anti-oxidant properties and indirect beneficial effects against cholestasis-induced toxicity during pregnancy, such as the enhanced expression of several elements of the anti-oxidant defence system, i.e. BVRα, SVCT1 and SVCT2, as well as several nuclear receptors sensitive to activation by biliary compounds [100] . This function is mainly dependent on the expression of BVRα, which has been found to be moderately up-regulated in the maternal liver-placenta-fetal liver trio in pregnant rats with surgically induced obstructive cholestasis during the last week of gestation [100] .…”

“…BVRα, SVCT1 and SVCT2, as well as several nuclear receptors sensitive to activation by biliary compounds [100] . This function is mainly dependent on the expression of BVRα, which has been found to be moderately up-regulated in the maternal liver-placenta-fetal liver trio in pregnant rats with surgically induced obstructive cholestasis during the last week of gestation [100] . However, beneficial antioxidant properties are limited to low bilirubin concentrations because at higher levels this pigment can also cause irreversible damage or even death when it is accumulated in the nervous system [101] .…”