Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration

Abstract

The identification of NOX4 as a major source of oxidative stress in stroke and demonstration of dramatic protection after stroke in mice by NOX4 deletion or NOX inhibition, opens up new avenues for treatment.

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

“…For these reasons, we wanted to test in vitro the potential antitumor efficiency of VAS2870, the only validated low-molecular weight pharmacological NOX inhibitor [13,24].…”

“…This fact might also suggest that NADPH oxidases are acting downstream tyrosine kinase receptors. It is worthy to note that VAS2870 inhibitory effect on NOX enzymes is not isoform-specific [13] and the final result might be a combinative effect of inhibiting all the isoforms expressed in the cell. The response to VAS2870 in the human HCC cell lines included in our study, whose NADPH oxidase expression pattern is more complex than the one detected for FaO cells, indicate the relevance of the proliferative role of NOXes in human liver tumor cells, Indeed, a role for NOX3 in the proliferative response to insulin has been reported in HepG2 cells [27].…”

“…Since we have previously demonstrated that NOX1 silencing by a siRNA approach could inhibit autocrine growth [9], we wanted to test the efficiency of the NADPH oxidases pharmacological inhibition in the same experimental conditions. For this purpose, we decided to use the Vasopharm BIOTECH GmbH drug VAS2870, a pharmacological NOX inhibitor, which has been useful to inhibit NADPH oxidases in preclinical assays both in vitro and in vivo [12,13].This compound showed a dosedependent inhibitory effect on cell growth in FaO cells ( Fig. 2A), which was maximal at the 25 M dose.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Treatment of endothelial cells with NOX4 siRNA decreased LPS induced migration and adhesion of monocytes by 36% and 52%, respectively (335). Increased NOX4 activity is also a reported risk factor in the progression of type-2 diabetic nephropathy, stroke, pulmonary fibrosis, and atherosclerotic lesions (11,145,219,240,331,382). However, the contradictory reports in the literature suggest that NOX4 is a vascular protective enzyme rather than a destructive one (415).…”

Vascular Nox4

“…In models of transient or permanent stroke, Nox4-deficient mice and mice treated with the Nox4 inhibitor VAS2870 were protected from oxidative stress, blood-brain barrier leakage, and neuronal apoptosis. 17 These data suggest that Nox4 is a major source of reactive oxygen species in ischemic stroke and that inhibition of Nox4 may be a strategy for stroke therapy. 17 To reconcile the growing confusion in the field, a number of considerations warrant further discussion.…”