NOX Inhibitors as a Therapeutic Strategy for Stroke and Neurodegenerative Disease

Belinda      Cairns; Jong      Youl Kim; Xian      Nan Tang; Midori      A. Yenari

Abstract

NADPH oxidase was originally identified in immune cells as playing an important microbicidal role. In neurodegenerative and cerebrovascular diseases, inflammation is increasingly being recognized as contributing negatively to neurological outcome, with NADPH-oxidase as an important source of superoxide. Recently, several forms of this oxidase have been found in a variety of non-immune cells. Neuronal NADPH oxidase is thought to participate in longterm potentiation and intercellular signaling. However, excessive superoxide production is damaging and has been shown to play an important role in the progression of brain injury. NADPH oxidase is a multisubunit complex composed of membrane-associated gp91phox and p22phox subunits and cytosolic subunits, p47phox, p67phox, and p40phox and Rac. When NADPH oxidase is activated through phosphorylatoin of p47phox, cytosolic subunits translocate to the cell membrane and fuse with the catalytic subunit, gp91phox. The activated enzyme complex transports electrons to oxygen, thus producing the superoxide anion (O2 – ), a precursor of reactive oxygen species. The advantage of a targeted NADPH oxidase inhibitor that would inhibit the production of superoxide non-phagocytic cells is clear. To date no such therapeutically viable inhibitor exists but recent research using current inhibitors has enhanced our knowledge of the role of NADPH oxidase in CNS diseases and provides impetus to develop a very specific, potent and safe NADPH oxidase inhibitor.

Keywords: Ischemia, superoxide, NADPH oxidase, NOX inhibitors, stroke, Neurodegenerative Disease, ROS, CNS, cerebrovascular disease, NADPH inhibitor