Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury
Hannah Mason,
Ganesha Rai,
Arina Kozyr,
Nathaniel De Jonge,
Emily Gliniewicz,
Lars J. Berg,
Gal Wald,
Cayce Dorrier,
Mark J. Henderson,
Alexey Zakharov,
Tristan Dyson,
John Audley,
Anthony M. Pettinato,
Elias Carvalho Padilha,
Pranav Shah,
Xin Xu,
Thomas L. Leto,
Anton Simeonov,
Kol A. Zarember,
Dorian B. McGavern,
John I. Gallin
Affiliations
Hannah Mason
Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA
Ganesha Rai
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
Arina Kozyr
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Nathaniel De Jonge
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Emily Gliniewicz
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Lars J. Berg
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Gal Wald
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Cayce Dorrier
Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA
Mark J. Henderson
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
Alexey Zakharov
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
Tristan Dyson
Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA
John Audley
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Anthony M. Pettinato
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Elias Carvalho Padilha
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
Pranav Shah
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
Xin Xu
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
Thomas L. Leto
Molecular Defenses Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
Anton Simeonov
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
Kol A. Zarember
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA; Corresponding author.
Dorian B. McGavern
Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA; Corresponding author.
John I. Gallin
Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA; Corresponding author.
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.
