Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury.
Publication/Presentation Date
4-1-2023
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.
Volume
60
First Page
102611
Last Page
102611
ISSN
2213-2317
Published In/Presented At
Mason, H., Rai, G., Kozyr, A., De Jonge, N., Gliniewicz, E., Berg, L. J., Wald, G., Dorrier, C., Henderson, M. J., Zakharov, A., Dyson, T., Audley, J., Pettinato, A. M., Padilha, E. C., Shah, P., Xu, X., Leto, T. L., Simeonov, A., Zarember, K. A., McGavern, D. B., … Gallin, J. I. (2023). Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury. Redox biology, 60, 102611. https://doi.org/10.1016/j.redox.2023.102611
Disciplines
Medicine and Health Sciences
PubMedID
36709665
Department(s)
Fellows and Residents
Document Type
Article