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

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.

SUBMITTER: Mason H

PROVIDER: S-EPMC9894920 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Mason Hannah H Rai Ganesha G Kozyr Arina A De Jonge Nathaniel N Gliniewicz Emily E Berg Lars J LJ Wald Gal G Dorrier Cayce C Henderson Mark J MJ Zakharov Alexey A Dyson Tristan T Audley John J Pettinato Anthony M AM Padilha Elias Carvalho EC Shah Pranav P Xu Xin X Leto Thomas L TL Simeonov Anton A Zarember Kol A KA McGavern Dorian B DB Gallin John I JI

Redox biology 20230118

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 m ...[more]

PMID: 36709665

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Project description:UnlabelledMore than 6.5 million patients are burdened by the physical, cognitive, and psychosocial deficits associated with traumatic brain injury (TBI) in the U.S. Despite extensive efforts to develop neuroprotective therapies for this devastating disorder, there have been no successful outcomes in human clinical trials to date. Retrospective studies have shown that β-adrenergic receptor blockers, specifically propranolol, significantly decrease mortality of TBI through mechanisms not yet fully elucidated but are thought to counterbalance a hyperadrenergic state resulting from a TBI. Conversely, cellular therapies have been shown to improve long-term behavior following TBI, likely by reducing inflammation. Given the nonredundancy in their therapeutic mechanisms, we hypothesized that a combination of acute propranolol followed by mesenchymal stem cells (MSCs) isolated from human bone marrow would have additive effects in treating a rodent model of TBI. We have found that the treatments are well-tolerated individually and in combination with no adverse events. MSCs decrease BBB permeability at 96 hours after injury, inhibit a significant accumulation of activated microglia/macrophage in the thalamic region of the brain both short and long term, and enhance neurogenesis short term. Propranolol decreases edema and reduces the number of fully activated microglia at 7 days and the number of semiactivated microglia at 120 days. Combinatory treatment improved cognitive and memory functions 120 days following TBI. Therefore, the results here suggest a new, efficacious sequential treatment for TBI may be achieved using the β-blocker propranolol followed by MSC treatment.SignificanceDespite continuous efforts, traumatic brain injury (TBI) remains the leading cause of death and disability worldwide in patients under the age of 44. In this study, an animal model of moderate-severe TBI was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short- and long-term measurements. These results have direct translational application. They reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation. More importantly, these results demonstrate that MSCs and propranolol, which is increasingly being used clinically for TBI, are compatible treatments that improve overall outcome.

Project description:RationalePersons with obstructive sleep apnea may have significant residual hypersomnolence, despite therapy. Long-term hypoxia/reoxygenation events in adult mice, simulating oxygenation patterns of moderate-severe sleep apnea, result in lasting hypersomnolence, oxidative injury, and proinflammatory responses in wake-active brain regions. We hypothesized that long-term intermittent hypoxia activates brain NADPH oxidase and that this enzyme serves as a critical source of superoxide in the oxidation injury and in hypersomnolence.ObjectivesWe sought to determine whether long-term hypoxia/reoxygenation events in mice result in NADPH oxidase activation and whether NADPH oxidase is essential for the proinflammatory response and hypersomnolence.MethodsNADPH oxidase gene and protein responses were measured in wake-active brain regions in wild-type mice exposed to long-term hypoxia/reoxygenation. Sleep and oxidative and proinflammatory responses were measured in adult mice either devoid of NADPH oxidase activity (gp91phox-null mice) or in which NADPH oxidase activity was systemically inhibited with apocynin osmotic pumps throughout hypoxia/reoxygenation.Main resultsLong-term intermittent hypoxia increased NADPH oxidase gene and protein responses in wake-active brain regions. Both transgenic absence and pharmacologic inhibition of NADPH oxidase activity throughout long-term hypoxia/reoxygenation conferred resistance to not only long-term hypoxia/reoxygenation hypersomnolence but also to carbonylation, lipid peroxidation injury, and the proinflammatory response, including inducible nitric oxide synthase activity in wake-active brain regions.ConclusionsCollectively, these findings strongly support a critical role for NADPH oxidase in the lasting hypersomnolence and oxidative and proinflammatory responses after hypoxia/reoxygenation patterns simulating severe obstructive sleep apnea oxygenation, highlighting the potential of inhibiting NADPH oxidase to prevent oxidation-mediated morbidities in obstructive sleep apnea.

Dataset Information

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

Publications

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

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