NADPH Oxidases in Neurodegenerative Disorders: Mechanisms and Therapeutic Opportunities
Targeting NOX Enzymes at the Source of Oxidative Stress
Oxidative stress sits at the centre of many of the intracellular dysfunctions that drive neurodegeneration, and this review sets out to clarify where the NADPH oxidase (NOX) enzyme family fits into that picture. While mitochondria have long been regarded as the primary source of reactive oxygen species (ROS) in the brain, the authors focus on NOX enzymes as an additional and specific source, examining how the different isoforms are regulated, where they are located in the central nervous system, and how their excessive activity contributes to disease. The analysis is organised around four disorders that together carry an enormous clinical and social burden: Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and stroke.
Building on this framework, the review describes how each NOX isoform behaves across these conditions. NOX1, NOX2, and NOX4 emerge as the isoforms most relevant to the brain, with NOX2 and NOX4 also prominent in the neurovascular context of stroke. In Parkinson’s disease in particular, the authors connect NOX1-mediated and NOX2-mediated oxidative stress to dopaminergic neurodegeneration and to alpha-synucleinopathy, drawing on toxin-based experimental models and on their own prior work in the field. Across all four disorders, a frequent pattern emerges in which NOX-derived ROS feed a self-reinforcing cycle of neuroinflammation, protein aggregation, mitochondrial dysfunction, and neuronal death.
From these mechanisms the authors argue that controlled inhibition of the NOX system, rather than its complete abrogation, could become a disease-modifying strategy that acts directly on the brain’s source of oxidative stress. They note that many NOX-targeting compounds have struggled to advance through development because of limited selectivity, off-target effects, and poor brain bioavailability, and they highlight two directions that could help overcome these obstacles: inhibitors designed for lower, more physiological levels of inhibition, and delivery routes that preferentially reach the brain while sparing peripheral tissues. In this regard, they point to the intranasal route as a promising administration strategy for brain-targeted therapies. Altogether, the review positions NOX inhibition as an approach aligned with the wider move towards precise, mechanism-specific therapies for neurodegenerative and neurological diseases.