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

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dc.contributor.authorJuric, Matea
dc.contributor.authorRawat, Varun
dc.contributor.authorAmaradhi, Radhika
dc.contributor.authorZielonka, Jacek
dc.contributor.authorGanesh, Thota
dc.date.accessioned2023-09-27T12:36:09Z
dc.date.available2023-09-27T12:36:09Z
dc.date.issued2023-08-23
dc.date.updated2023-09-27T12:36:11Z
dc.description.abstractA 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.
dc.description.departmentCenter for Innovative Drug Discovery
dc.identifierdoi: 10.3390/antiox12091660
dc.identifier.citationAntioxidants 12 (9): 1660 (2023)
dc.identifier.urihttps://hdl.handle.net/20.500.12588/2072
dc.rightsAttribution 4.0 United States
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectNADPH oxidase
dc.subjectinflammation
dc.subjectneurodegeneration
dc.subjectinhibitors
dc.subjectneuroprotection
dc.subjectsuperoxide
dc.subjecthydrogen peroxide
dc.titleNovel NADPH Oxidase-2 Inhibitors as Potential Anti-Inflammatory and Neuroprotective Agents
dc.typeArticle

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