Decoding Oxidative Stress: Novel Mechanistic Pathways In Neurodegeneration

Abstract

Oxidative stress (OS) represents a pathological imbalance between pro-oxidant production and antioxidant defense systems, resulting in the excessive accumulation of reactive oxygen species (ROS) and subsequent molecular damage. Although low physiological levels of ROS are essential for cellular signaling, synaptic plasticity, and immune responses, sustained ROS overproduction disrupts redox homeostasis. It induces oxidative damage to lipids, proteins, and nucleic acids. The brain is particularly vulnerable to oxidative injury because of its high oxygen consumption, abundant lipid content, and comparatively limited antioxidant capacity. Mounting evidence implicates oxidative stress as a central contributor to the pathogenesis of major neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and epilepsy. Shared mechanisms include mitochondrial dysfunction, impaired antioxidant defenses, excitotoxicity, neuroinflammation, and protein aggregation, while disease- specific pathways involve dopamine quinone toxicity in PD, mutant SOD1-associated redox imbalance in ALS, amyloid-β-mediated metal catalysis in AD, and mutant huntingtin-induced mitochondrial injury in HD. Biomarkers such as F2-isoprostanes, malondialdehyde, protein carbonyls, 3- nitrotyrosine, and 8-hydroxy-2′-deoxyguanosine provide measurable indices of oxidative damage, though their clinical translation remains limited. This review critically evaluates the mechanistic evidence linking oxidative stress to neurodegeneration, distinguishes oxidative stress from oxidative damage, and discusses the translational challenges associated with antioxidant-based therapeutic strategies.