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Author Notes:

Contributions: Matea Juric: Validation, Formal analysis, Investigation, Writing – review & editing Varun Rawat: Validation, Formal analysis, Investigation, Writing – review & editing, Visualization M.J and V.R. equally contributed to this work. Radhika Amaradhi: Investigation, Writing – review & editing Jacek Zielonka: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition Thota Ganesh: Conceptualization, Methodology, Validation, Resources, Data curation, Writing – original draft, Writing – review & editing, Supervision, Project administration, Funding acquisition Conceptualization, T.G. and J.Z.; methodology, J.Z. and T.G.; validation, M.J., V.R., J.Z. and T.G.; formal analysis, M.J., V.R. and J.Z.; investigation, M.J., V.R., R.A. and J.Z.; resources, T.G. and J.Z.; data curation, T.G. and J.Z.; writing—original draft preparation, J.Z. and T.G.; writing—review and editing, M.J., V.R., R.A., J.Z. and T.G.; visualization, J.Z. and V.R.; supervision, J.Z. and T.G.; project administration, J.Z. and T.G.; funding acquisition, J.Z. and T.G.

Acknowledgments: J.Z. thanks B. Kalyanaraman (Medical College of Wisconsin) for providing access to the plate readers and HPLC instruments for the completion of this study.

Conflicts of Interest T.G., J.Z. and R.A. are inventors of patent application Quinazoline derivatives, pharmaceutical compositions, and therapeutic uses related to Nox inhibition (WO2022225866A1).

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Research Funding:

This work was supported by NIH/NIA grant U01 AG052460 (T.G.). The liquid handling equipment used to monitor the Nox2 inhibitory activity of the compounds tested was purchased using funds from the Advancing a Healthier Wisconsin Endowment (project 5520583: Small Volume Multi-well Plate Dispensers for Screening Drug Combinations) awarded to J.Z.

Keywords:

  • NADPH oxidase
  • inflammation
  • neurodegeneration
  • inhibitors
  • neuroprotection
  • superoxide
  • hydrogen peroxide

Novel NADPH Oxidase-2 Inhibitors as Potential Anti-Inflammatory and Neuroprotective Agents

Tools:

Journal Title:

antioxidants

Volume:

Volume 12, Number 9

Publisher:

, Pages 1660-None

Type of Work:

Article | Final Publisher PDF

Abstract:

A family of seven NADPH oxidase enzymes (Nox1-5, Duox1-2) has been implicated in a variety of diseases, including inflammatory lung diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Here, we report the results of our studies aimed at developing novel brain-permeable Nox2 inhibitors with potential application as neuroprotective agents. Using cell-based assays, we identified a novel Nox2 inhibitor, TG15-132, that prevents PMA-stimulated oxygen consumption and reactive oxygen species (superoxide radical anion and hydrogen peroxide) formation upon acute treatment in differentiated HL60 cells. Long-term treatment with TG15-132 attenuates the induction of genes encoding Nox2 subunits, several inflammatory cytokines, and iNOS in differentiated THP-1 cells. Moreover, TG15-132 shows a relatively long plasma half-life (5.6 h) and excellent brain permeability, with a brain-to-plasma ratio (>5-fold) in rodent models. Additionally, TG15-132 does not cause any toxic effects on vital organs or blood biomarkers of toxicity in mice upon chronic dosing for seven days. We propose that TG15-132 may be used as a Nox2 inhibitor and a potential neuroprotective agent, with possible further structural modifications to increase its potency.

Copyright information:

© 2023 by the authors. Licensee MDPI, Basel, Switzerland.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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