2. Academic Validation
  3. Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury

Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury

  • Redox Biol. 2023 Apr:60:102611. doi: 10.1016/j.redox.2023.102611.
Hannah Mason 1,  Ganesha Rai 2,  Arina Kozyr 3,  Nathaniel De Jonge 3,  Emily Gliniewicz 3,  Lars J Berg 3,  Gal Wald 3,  Cayce Dorrier 4,  Mark J Henderson 2,  Alexey Zakharov 2,  Tristan Dyson 4,  John Audley 3,  Anthony M Pettinato 3,  Elias Carvalho Padilha 2,  Pranav Shah 2,  Xin Xu 2,  Thomas L Leto 5,  Anton Simeonov 2,  Kol A Zarember 6,  Dorian B McGavern 7,  John I Gallin 8
Affiliations

Affiliations

  • 1 Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address: hannah.mason@emory.edu.
  • 2 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • 3 Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA.
  • 4 Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 5 Molecular Defenses Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA.
  • 6 Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA. Electronic address: kzarember@niaid.nih.gov.
  • 7 Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address: mcgavernd@ninds.nih.gov.
  • 8 Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA. Electronic address: jig@nih.gov.
PMID: 36709665 DOI: 10.1016/j.redox.2023.102611
Abstract

NADPH oxidases (NOX's), and the Reactive Oxygen Species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, Apoptosis, gene regulation, angiogenesis and Other processes. However, overproduction of ROS by these Enzymes is associated with Cardiovascular Disease, fibrosis, traumatic brain injury (TBI) and Other Diseases. Structural similarities between NOX's have complicated development of specific inhibitors. Here, we report development of NCATS-SM7270, a small molecule optimized from GSK2795039, that inhibited NOX2 in primary human and mouse granulocytes. NCATS-SM7270 specifically inhibited NOX2 and had reduced inhibitory activity against Xanthine Oxidase in vitro. We also studied the role of several NOX isoforms during mild TBI (mTBI) and demonstrated that NOX2 and, to a lesser extent, NOX1 deficient mice are protected from mTBI pathology, whereas injury is exacerbated in NOX4 knockouts. Given the pathogenic role played by NOX2 in mTBI, we treated mice transcranially with NCATS-SM7270 after injury and revealed a dose-dependent reduction in mTBI induced cortical cell death. This inhibitor also partially reversed cortical damage observed in NOX4 deficient mice following mTBI. These data demonstrate that NCATS-SM7270 is an improved and specific inhibitor of NOX2 capable of protecting mice from NOX2-dependent cell death associated with mTBI.

Keywords

Inhibitor; Mouse; NADPH Oxidase; Traumatic brain injury.

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