NOX Inhibitors as a Therapeutic Strategy for Stroke and Neurodegenerative Disease

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 long-term 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 gp91(phox) and p22(phox) subunits and cytosolic subunits, p47(phox), p67(phox), and p40(phox) and Rac. When NADPH oxidase is activated through phosphorylatoin of p47(phox), cytosolic subunits translocate to the cell membrane and fuse with the catalytic subunit, gp91(phox). The activated enzyme complex transports electrons to oxygen, thus producing the superoxide anion (O-2(center dot)), 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.