Esomeprazole counteracts chlorine toxicity in pregnant animals

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We have shown that pregnant mice are particularly susceptible to injury caused by Br2 exposure and develop symptoms that are reminiscent of preeclampsia. We identified placental production of a short splice variant of FMS-like tyrosine kinase 1 (sFLT-1) and consequent inhibition of signaling via vascular endothelial growth factor (VEGF) as an underlying mechanism. Additionally, treatment with the type V phosphodiesterase inhibitor (PDE5i) tadalafil or treatment with recombinant VEGF mitigate pregnancy-specific Br2 toxicty by reducing blood pressure, restoring heart function, reducing respiratory and metabolic acidosis and reducing lung edema. In preliminary data, we demonstrate that Cl2 exposure is highly toxic to pregnant mice, resulting in severe maternal weight loss, high rate of maternal mortality and severe fetal growth restriction. Additional preliminary data show that treatment with the proton pump inhibitor (PPI) esomeprazole (ESO; 30 mg/kg/day by gavage), which is the active ingredient of Nexium®, results in improved maternal weight gain and fetal growth in Cl2 exposed pregnant mice. ESO is a PPI, but was found to stimulate nuclear factor (erythroid-derived 2)–like 2 (Nrf2), resulting in the increased expression of antioxidant genes including HO-1 as well. HO-1 is critical for the development and maintenance of normal pregnancy. Stimulation of HO-1 expression has been shown to antagonize mechanisms that cause preeclampsia and ameliorate diagnostic signs of preeclampsia in animal models. Our specific aims were designed to test the hypothesis that ESO (30 mg/kg/day by gavage) improves survival and fetal growth by inducing HO-1 via activation of nuclear factor (erythroid-derived 2)–like 2 (Nrf2) and the protective effects will be accompanied by reduced mediators and symptoms of preeclampsia that occur in Cl2 exposed pregnant mice. To test these proposed mechanisms, we will compare the efficacy of ESO to another, FDA-approved Nrf2 activator dimethyl fumarate (DMF; Tecfidera®) and we will assess the effects of the chemical inhibitors of Nrf2 (ML385) and HO-1 (tin proto porphyrin IX; SnPP) on the efficacy of ESO. SA#1: To compare the efficacy of ESO (30 mg/kg/day by gavage) with DMF (100 mg/kg/day by gavage) to reduce maternal mortality, fetal growth restriction and symptoms of preeclampsia in Cl2 exposed pregnant mice. DMF is an FDA approved drug for the treatment of multiple sclerosis. Similar to ESO, DMF is known to activate Nrf2, but it is not a proton pump inhibitor. Comparing the efficacy of ESO to DMF will allow to dissociate the mechanistic contribution of Nrf2 activation from the PPI function of ESO. SA#2 To test the mechanistic roles of Nrf2 activation and HO- 1 activity in protection from Cl2 exposure toxicity by ESO. We will use the small molecule inhibitors of Nrf2 (ML385) and HO-1 (tin protoporphyrin IX; SnPP) for mechanistic testing. Success of this research plan will be the basis of a full application (UO1) for the testing of dose-dependent efficacy of ESO and/or DMF against both Cl2 and Br2 induced pathology in pregnant mice, including the continuous monitoring of blood pressure with telemetry, and additional mechanistic studies using Nrf2 and HO-1 gene-targeted murine models.