Abstract

Diabetes mellitus is associated with accelerated neuronal injury manifesting as diabetic peripheral neuropathy, 
cognitive impairment, and heightened risk of neurodegenerative disease. A large body of evidence implicates 
oxidative stress-the imbalance between production of reactive oxygen and nitrogen species (ROS/RNS) and 
antioxidant defenses a central mediator linking hyperglycaemia, dyslipidaemia, and chronic inflammation to 
neuronal dysfunction. Hyperglycaemia-driven metabolic pathways (polyol flux, advanced glycation end-products, 
protein kinase C activation, hexosamine pathway), mitochondrial overload, NADPH oxidase activation, and 
inflammation converge on excessive ROS/RNS generation, which in turn damages neuronal macromolecules, 
perturbs ion homeostasis, impairs axonal transport and mitochondrial dynamics, and triggers neuroinflammation. 
Translational research has explored a range of neuroprotective strategies tight metabolic control, repurposed 
antidiabetic drugs with pleiotropic antioxidant effects, nutraceutical and polyphenol interventions, Nrf2 pathway 
activators, mitochondria-targeted antioxidants, and novel drug-delivery systems-to interrupt the oxidative cascade. 
While preclinical studies show consistent neuroprotection by redox-targeted interventions, clinical translation has 
been mixed due to heterogeneity in patient populations, timing of intervention, bioavailability of compounds, and 
limited biomarker-guided stratification. Future progress requires biomarker-driven trials, mitochondrial- and 
blood–brain-barrier–targeted delivery, and combination therapies that preserve physiological ROS signalling while 
preventing pathological oxidative damage. This review synthesizes current mechanistic insights into oxidative 
stress–mediated neurotoxicity in diabetes and evaluates the evidence and potential of neuroprotective interventions.