Research

Preeclampsia Pathogenesis and Our Drug Candidates

Updated ROS Graphic

Schematic of human preeclampsia development and targeted therapies. The first stage of preeclampsia is characterized by abnormal placentation due to defective remodeling of the uterine spiral arteries, which will induce placental ischemia. We and others have proposed that this ischemic state will impair trophoblast mitochondrial function including energy production. The damaged mitochondria will release reactive oxygen species (ROS/RNS). ROS can stabilize hypoxia inducible factor (HIF-1α), which will induce transcription of anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) , as well as protective angiogenic factors as VEGF and placental growth factor, PlGF. The anti-angiogenic factors are released into the maternal circulation, and their actions disrupt the maternal endothelium and result in hypertension, proteinuria, and other systemic manifestations of preeclampsia. The top right inset shows increased red fluorescence, indicating the presence of ROS in the human PE placenta compared to the control (gestationally age-matched) placenta (on the left. The middle inset shows increased brown staining (nitrotyrosine) in the human PE placenta (on the right), which indicates the presence of RNS in the PE placenta compared to the control (gestationally age-matched) placenta (on the left). Bottom inset: Functional electron microscopy: Mitochondrial electron transport chain enzyme: Cytochrome C Oxidase (COX) enzyme activity is decreased in placental villous trophoblasts in preeclampsia, suggesting mitochondrial dysfunction (Right panel), compared to control placenta (on the left).

Drug groups and their benefits: 

1.  Organofluorine hydrazones: i, due to its high electronegativity, F atoms increase the antioxidant efficacy. ii, based on the high stability of the C-F bonds, these compounds are resistant to metabolic degradation, thus allowing lower doses. iii, the fluorine incorporation is known to increase lipophilicity and improve membrane permeability. iv, the molecules will be active in 19F NMR spectroscopy, and this selective technique can be applied for pharmacokinetic studies.

2.  AKT-1005 and analogs will target both the imbalance in oxygen-centered and nitrogen-centered free radicals, and the maternal hypertension, thereby acting on multiple components underlying the pathophysiology of preeclampsia

3.  Slow-release mitochondria-targeted H2S donors (mtH2SD) are 1,000 —10,000 more potent than non-targeted H2S donors. As we reported theyare capable of stimulating mitochondrial respiration and ATP synthesis, while also preventing oxidant production and mtDNA damage in an in vitro model of PE.

Therapies that specifically treat the underlying causes at an early stage of pregnancy could prevent the serious, even fatal organ dysfunction and eclampsia that characterizes preeclampsia.

 

 

Recent Publications and Patent Information

Patent Application:

USSN: 63/758,631     HYDRAZONES AS THERAPEUTICS FOR MITOCHONDIAL OXIDATIVE STRESS DISORDERS

PI: Zsengeller, Zsuzsanna K, Torok, Marianna and Torok, Bela

Publications:

  • Mastyugin, Maxim, Bernadett Vlocskó, Zsuzsanna K. Zsengellér, Béla Török, and Marianna Török. 2025. Development of Diaryl Hydrazones for Alleviation of Mitochondrial Oxidative Stress in Preeclampsia. Journal of Medicinal Chemistry .
    Publisher's Version

    Preeclampsia is a pregnancy-specific syndrome, linked to oxidative stress, affecting 5-8% of pregnancies, with no effective treatment available. Here, diaryl-hydrazones have been designed, synthesized, and investigated as mitochondria-targeting antioxidants to reduce placental oxidative stress and mitigate preeclampsia symptoms. The design, based on density functional theory studies, revealed that conjugated electron structure with the NH-motif appeared to explain their effect. Thirty compounds were synthesized and tested in three assays, where they exhibited excellent radical scavenging activity, significantly greater than that of the standard, Trolox. Based on the data, eight compounds were selected for cell-based assays. Oxidative stress was induced in human trophoblast cells and assessed whether the compounds reduced downstream antiangiogenic responses using ascorbic acid and MitoTEMPO as standards. The pretreatment with the hydrazones reduced mitochondrial superoxide and sFLT-1 production in H2O2-exposed trophoblast cells, indicating that mitochondrial oxidative stress and the anti-angiogenic response can be alleviated by these compounds.

  • Pintye, Diana, Réka E Sziva, Maxim Mastyugin, Brett C Young, Sonako Jacas, Marianna Török, Saira Salahuddin, Prakash Jagtap, Garry J Southan, and Zsuzsanna K Zsengeller. 2023. “A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia-Relevance for Preeclampsia Therapy..”
    Publisher's Version

    Preeclampsia (PE) is a severe, life-threatening complication during pregnancy (~5-7%), and no causative treatment is available. Early aberrant spiral artery remodeling is associated with placental stress and the release of oxygen radicals and other reactive oxygen species (ROS) in the placenta. This precedes the production of anti-angiogenic factors, which ultimately leads to endothelial and trophoblast damage and the key features of PE. We tested whether a novel dual-function redox modulator-AKT-1005-can effectively reduce placental oxidative stress and alleviate PE symptoms in vitro. Isolated human villous explants were exposed to hypoxia and assessed to determine whether improving cell-redox function with AKT-1005 diminished ROS production, mitochondrial stress, production of the transcription factor HIF1A, and downstream anti-angiogenic responses (i.e., sFLT1, sEng production). MitoTEMPO was used as a reference antioxidant. In our villous explant assays, pretreatment with AKT-1005 reduced mitochondrial-derived ROS production, reduced HIF-1A, sFLT1, and sEng protein expression, while increasing VEGF in hypoxia-exposed villous trophoblast cells, with better efficiency than MitoTEMPO. In addition, AKT-1005 improved mitochondrial electron chain enzyme activity in the stressed explant culture. The redox modulator AKT-1005 has the potential to intervene with oxidative stress and can be efficacious for PE therapy. Future studies are underway to assess the in vivo efficacy of HMP.