NADPH oxidases (NOX), catalyzing the reduction of molecular oxygen to form the superoxide radical anion (O₂⁻) and hydrogen peroxide (H₂O₂). NOX involves in several pathological conditions, such as stroke, diabetes, atherosclerosis, but also in chronic neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, or multiple sclerosis. Especially, NOX are the only enzyme family known to generate ROS as their sole function. There are seven paralogues of the NOX family, comprising NOX1-5 and dual oxidase 1/2 (DUOX1/2) in mammalian cells. In addition, NOX plays a central role in modulating various CNS diseases, and NOX inhibitors have shown neuroprotective effects in different neurodegenerative disorders. GKT136901 is a highly selective small molecule inhibitor of NOX1 and NOX4.
NOX4 highly expresses in the vasculature after brain injury. Inhibition of NOX4 with GKT136901 inhibits the apoptosis of type II epithelial cells induced by TGF‐β. GKT136901 attenuates Methamphetamine-induced oxidative stress in human brain microvascular endothelial cells (HBMECs). In addition, GKT136901 protects HBMECs against Methamphetamine-induced blood-brain barrier (BBB) dysfunction. GKT136901 restores intercellular junctions in Methamphetamine-exposed HBMECs. Moreover, GKT136901 attenuates Methamphetamine-induced cytoskeletal rearrangement in HBMECs. Compared to other NOX inhibitors, GKT136901 has good oral bioavailability, suggesting that NOX1/4 inhibition using GKT136901 could provide a safe and effective therapeutic approach for CNS diseases.
The crucial role of NOX4 in BBB disruption leads to neurodegenerative disorders. GKT136901 might protects the brain endothelium against Methamphetamine-induced BBB dysfunction. Furthermore, GKT136901 protects primary human brain microvascular endothelial cells against Methamphetamine-induced blood-brain barrier dysfunction.
In summary, GKT136901 is a selective and direct scavenger of peroxynitrite. GKT136901 protects primary human brain microvascular endothelial cells against Methamphetamine-induced blood-brain barrier dysfunction.
G Teixeira, et al. Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol. 2017 Jun;174(12):1647-1669.