61 Melatonin supplementation prevents endothelial cell activation, possible relevance to preeclampsia

Abstract

Introduction Preeclampsia, a human pregnancy-specific disease, is a leading cause of maternal and perinatal mortality and morbidity. It is characterised by maternal endothelial cell dysfunction. Although the exact causes of this disease are unclear, it is thought that there is an increase in oxidative stress in the placenta and leading to the release of a toxic factor (s) from the placenta that triggers maternal endothelial cell activation. Endothelial cell activation precedes the clinical signs and symptoms of the maternal syndrome of preeclampsia. Trophoblast debris, which is shed from the placenta into the maternal blood, is hypothesised to be one such trigger. Our previous studies showed that treating placentae with antiphospholipid antibodies (aPL), which increase the risk of women developing preeclampsia 10 fold [1, 2], or preeclamptic sera, results in the production of toxic trophoblastic debris which induces endothelial cell activation [3]. Melatonin is a lipid soluble hormone originally found to be released by the pineal gland but which has been shown to have antioxidant activities and to be produced in the placenta. Given the action of melatonin in regulating oxidative stress and cell death, we investigated whether melatonin supplementation can reverse the effects of preeclamptic sera or aPL on placental oxidative damage and the production of toxic trophoblastic debris. Methods First trimester placental explants were cultured with aPL (20 μ g/ml) or preeclamptic sera (n = 6) in the presence or absence of melatonin (1 μ M, 10 μ M) for 24 h. Trophoblastic debris was collected from the explants and then exposed to monolayers of endothelial cells (HMEC-1) for 24 h and cell surface ICAM-1 expression was measured by cell-based ELISA to determine endothelial cell activation. The expression of nitrotyrosine in placental explants that were treated with aPL or preeclamptic sera was measured by immunohistochemistry or western blotting. Results 1) Trophoblastic debris from placental explants that were treated with aPL or preeclamptic sera (n = 6) significantly (p 2) In contrast, trophoblastic debris from explants that were treated with aPL or preeclamptic sera in the presence of melatonin (n = 6) did not significantly increased the expression of ICAM-1 compared to control-treated endothelial cells 3) The expression of nitrotyrosine was significantly increased in placentae that had been treated with aPL or preeclamptic sera. However, this increase in levels of nitrotyrosine was not found in placental explants where aPL or PE sera were added in the presence of melatonin. Conclusions Our results suggest that there is oxidative damage induced in placentae by either aPL or preeclamptic sera and consequently trophoblastic debris produced by these placentae is more toxic to endothelial cells. Melatonin can reverse this placental oxidative damage and reduced the toxicity of the trophoblastic debris. Since the pathogenesis of preeclampsia is thought to be partially dependent on the maternal response to placental factors such as toxic trophoblastic debris shed from placentae, our results encouraging suggest that melatonin might be a useful tool to alleviate the clinical manifestations of preeclampsia.