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

Abstract

A 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.

Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration

“…The family of NADPH oxidase enzymes (Nox1-5, Duox1-2) has seven members, which are known to be involved in various diseases, such as inflammatory lung diseases, neurodegenerative diseases, and cancer. A novel Nox2 inhibitor, TG15-132, supports neuroprotection by blocking inflammatory responses, including the generation of reactive oxygen species and inflammatory cytokines [ 14 ]. Calebin-A is a natural polyphenol and a curcumin analog [ 15 , 16 , 17 , 18 ] ( Figure 1 ).…”

“…For example, WW1, possessing two tryptophan residues, binds proline-rich motifs PPXY or PPPY-containing target proteins for numerous biological functions during signaling [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Such events include cell death, differentiation, signaling, cell migration and recognition, and disease development [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. WW2 has one tryptophan, whose function has not been elucidated.…”