Significance: The growing incidence of
neurodegenerative diseases significantly impacts the individuals who suffer from these disorders and is a major health concern globally. Although the specific mechanisms of
neurodegenerative diseases are still far from being acknowledged, it is becoming clear that oxidative stress and
neuroinflammation are critical contributing factors to the progression of neurodegeneration. Thus, it is conceivable that the inhibition of oxidative stress and
neuroinflammation may represent promising therapeutic targets for the treatment of
neurodegenerative diseases. Recent Advances: Recently, the strategy for
neurodegenerative disease therapy has shifted from the use of
antioxidants and conventional anti-inflammatory targets to upstream mediators due to the failure of most
antioxidants and nonsteroidal anti-inflammatory drugs in clinical trials.
Nicotinamide adenine dinucleotide phosphate oxidases (NOXs), a family of
superoxide-producing
enzyme complexes, have been identified as an upstream factor that controls both oxidative stress and
neuroinflammation. Genetic inactivation or pharmacological inhibition of NOX
enzymes displays potent
neuroprotective effects in a broad spectrum of
neurodegenerative disease models. Critical Issues: The detailed mechanisms of how NOX
enzymes regulate oxidative stress and
neuroinflammation still remain unclear. Moreover, the currently available inhibitors of NOX
enzymes exhibit nonspecificity, off-target effects, unsuitable pharmacokinetic properties, and even high toxicity, markedly limiting their potential clinical applications. Future Directions: This review provides novel insights into the roles of NOXs in neurodegenerative pharmacology, and indicates the types of NOX
enzyme inhibitors that should be identified and developed as candidates for future applications, which might reveal novel
neurodegenerative disease therapies based on NOXs.