Endothelin-1 triggers placental oxidative stress pathways: putative role in preeclampsia

CONTEXT: Preeclampsia (PE) is a disorder that occurs only during pregnancy. The placenta has a controlling role in this condition. Recent literature suggests that the oxidative stress is a component of PE and plays a main role in the link between decreased placental perfusion and the impaired function of maternal endothelium. OBJECTIVE: Because the human placenta expresses endothelin-1 (ET-1) and its circulating levels are high in pregnancies complicated with PE, the present study investigated the role of ET-1 on placental oxidative stress pathways. DESIGN: Human placental explants, JEG-3, and primary cytotrophoblast cells were cultured with increasing ET-1 concentrations for 6 and 24 h. SETTING: The study was conducted at tertiary clinical care centers in Siena and Padova, Italy. INTERVENTIONS: Human placental explants, JEG-3, and primary cytotrophoblast cells were used to test ET-1 effect. MAIN OUTCOME MEASURE(S): The main outcome measure was ET-1 mRNA and its receptor mRNAs, type A and B, detection by RT-PCR. The common markers of oxidative stress [malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), ascorbic acid (AA)] as well as cell proliferation and vitality were measured after stimulation periods. RESULTS: ET-1 inhibits cell proliferation and vitality and triggers oxidative stress in the human placenta by altering the balance between oxidant (increased MDA levels) and antioxidant (decreased GSH, GSSG, and AA) forces in favor of oxidation. CONCLUSIONS: Because MDA damages endothelial cells, whereas GSH, GSSG, and AA protect them, we postulate that ET-1 may be one of the key links between primary placental disorders and the systemic endothelial dysfunction of PE.     

AIT-082 is neuroprotective against kainate-induced neuronal injury in rats

4-[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]benzoic acid (AIT-082) is an hypoxanthine derivative that stimulates in vitro neurite outgrowth and the production of adenosine and neurotrophins from astrocytes. These effects may predict an in vivo neuroprotective activity of the drug. Thus, we evaluated whether AIT-082 protected against a long-term excitotoxicity of hippocampal neurons following status epilepticus induced in rats by i.p. injection of kainate (12 mg/kg). The epileptogenic effect of kainate was evaluated by monitoring behavioral signs and by electroencephalographic (EEG) recording (80% of the animals showed status epilepticus with a latency of 96.8 +/- 7.4 min starting from the injection). In surviving rats (40% of the injected animals) the neurotoxic effect was evaluated by measuring glutamic acid decarboxylase (GAD) activity, as an index of loss of hippocampal GABAergic neurons, by evaluating the body weight after 7 days and by histological examination of hippocampi. The GAD activity was reduced by 44 +/- 8%, and neuronal loss (about 70%) was found in the CA3c, the CA1 area, and in the dentate gyrus. A single dose of diazepam (20 mg/kg; i.p., 20 min before the kainate injection) almost completely inhibited both seizures and neurotoxicity, ensuring survival of animals. AIT-082 (60 mg/kg/day; i.p., for 7 days, starting from 20 min before the kainate injection) did not modify the seizures caused by kainate but, like diazepam, it decreased kainate-induced mortality, the reduction of GAD activity, and the loss of hippocampal neurons. These data confirm that AIT-082 is of potential interest for the experimental therapy of neurodegenerative disorders.