Molecular Basis of Oxidative Stress in Neurodegenerative Disorders: Biochemical Insights and Antioxidant Strategies

Background: Oxidative stress is increasingly recognized as a pivotal contributor to the pathogenesis of neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease. The central nervous system is particularly vulnerable to redox imbalance due to its high oxygen consumption, abundant polyunsaturated lipids, and relatively low antioxidant capacity. Excessive production of reactive oxygen and nitrogen species (ROS/RNS) leads to irreversible damage to neuronal DNA, proteins, and lipids, exacerbating neuroinflammation, mitochondrial dysfunction, and synaptic degeneration. Methods and Results: This review explores the molecular underpinnings of oxidative stress in neurodegeneration, with emphasis on the biochemical mechanisms that drive redox imbalance and its downstream consequences. Mitochondrial electron transport chain dysfunction, NADPH oxidase activation, impaired antioxidant defense (e.g., glutathione depletion, SOD mutation), and disrupted iron homeostasis are key sources of ROS in neurons. Oxidative post-translational modifications, such as protein carbonylation and S-nitrosylation, alter the function of tau, α-synuclein, and other neuronal proteins, promoting aggregation and proteotoxicity. Additionally, redox-sensitive signaling pathways involving NF-κB, MAPKs, and Nrf2 modulate neuroinflammatory responses and antioxidant gene expression. Therapeutic interventions aimed at restoring redox homeostasis include small-molecule antioxidants (e.g., CoQ10, edaravone), gene therapies enhancing endogenous antioxidant enzymes, and dietary polyphenols with neuroprotective properties. Emerging nanocarriers and mitochondria-targeted delivery systems are being developed to improve therapeutic specificity and efficacy. Conclusion: Oxidative stress is a central biochemical driver of neuronal injury in neurodegenerative diseases. A mechanistic understanding of redox imbalance and its cellular consequences paves the way for antioxidant-based strategies that could slow or prevent neurodegenerative progression.