Mitochondria-targeting Novel Cationic Hydrazone Antioxidants for the Treatment of Preeclampsia

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SUMMARY Preeclampsia (PE) is a common, life-threatening complication in pregnancy, characterized by high blood pressure putting the mother at risk of eclampsia and kidney dysfunction. PE affects about 1–5% of pregnancies and a major cause of maternal and fetal deaths. The hallmarks of PE are the decrease in trophoblast invasion and abnormal remodeling of the spiral arteries; as well as an angiogenic/antiangiogenic imbalance. The abnormal placentation will, most likely, cause reduced feto- maternal blood flow and increased oxidative stress resulting in compromised function. There is no clear pathogenesis or cure, thus an effective treatment for PE is an unmet medical need. The primary goal of this proposal is to develop novel cationic organofluorine hydrazones for mitochondria-targeted antioxidant therapy in preeclampsia. Three key structural features will be combined to effective antioxidants: (i) a hydrazone core for improved antioxidant potential, (ii) fluorine incorporation for increased lipophilicity and membrane permeability, and (iii) introduction of quaternary ammonium salts (QASs) for the delivery of the lipophilic cation through the mitochondrial membrane. Based on our preliminary data and the results of in silico evaluations, we will design and synthesize QAS-containing organofluorine antioxidants that will be subjected to primary screening for their in vitro antioxidant activity in biochemical assays. The compounds that will show significant radical scavenging properties will be evaluated in cell-based and in vivo assays. Human primary trophoblast cells (normal or PE pregnancy) will be tested whether augmenting cell-redox function chemically by the proposed antioxidants will reduce (i) cell injury, (ii) mitochondrial stress, (iii) HIF1α production, and (iv) downstream anti-angiogenic response to hypoxia-reoxygenation. The same assays will also be carried out in human endothelial cells exposed to hypoxia-reoxygenation. In addition, time-pregnant mice will be subjected to hypoxia, to induce the main features of PE, (hypertension, proteinuria and oxidative stress), and treated with the synthetic antioxidants and the mice will be evaluated for blood pressure, renal function, histologic damage, 3-nitrotyrosine (3-NT) tissue immunoreactivity, inflammation markers and plasma biomarkers. Finally, mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy will be used to map the presence of the new cationic hydrazones in cells and tissues. These studies may lead to the development of new effective antioxidant compounds, which antagonize ROS/RNS that prevent the activation of the HIF1 pathway and therefore improve angiogenic balance and reduce the systemic effects of PE. Regarding the educational/training aspects, this work will provide a multi-environmental and interdisciplinary training to undergraduate students who will participate in each step of the project and be exposed to the research atmosphere at two different institutions.