Significance: The significant role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) in signal transduction is mediated by the production of reactive oxygen species (ROS), especially in the central nervous system (CNS). The pathogenesis of some neurologic and psychiatric diseases is regulated by ROS, acting as a second messenger or pathogen. Recent Advances: In the CNS, the involvement of Nox-derived ROS has been implicated in the regulation of multiple signals, including cell survival/apoptosis, neuroinflammation, migration, differentiation, proliferation, and synaptic plasticity, as well as the integrity of the blood/brain barrier. In these processes, the intracellular signals mediated by the members of the Nox family vary among different tissues. The present review illuminates the regions and cellular, subcellular localization of Nox isoforms in the brain, the signal transduction, and the role of NOX enzymes in pathophysiology, respectively. Critical Issues: Different signal transduction cascades are coupled to ROS derived from various Nox homologues with varying degrees. Therefore, a critical issue worth noting is the varied role of the homologues of NOX enzymes in different signaling pathways and also they mediate different phenotypes in the diverse pathophysiological condition. This substantiates the effectiveness of selective Nox inhibitors in the CNS. Future Directions: Further investigation to elucidate the role of various homologues of NOX enzymes in acute and chronic brain diseases and signaling mechanisms, and the development of more specific NOX inhibitors for the treatment of CNS disease are urgently needed. Antioxid. Redox Signal. 35, 951-973.
Keywords: NADPH oxidase; Nox inhibitors; neurodegeneration; neuroinflammation; signal transduction.