Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Neurodegenerative Diseases: Mechanisms and Therapy.

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.