Abstract

Diabetic neuropathy is a common, debilitating complication of diabetes characterized by sensory loss, neuropathic 
pain, and autonomic dysfunction. Oxidative stress is a central pathogenic driver, promoting neuronal damage, 
mitochondrial dysfunction, and maladaptive neuroinflammation. Natural antioxidants-plant-derived polyphenols, 
flavonoids, terpenoids, and other phytochemicals-exert pleiotropic effects beyond simple free-radical scavenging, 
including modulation of ion channels, neurotransmitter systems, neurotrophic signaling, and inflammatory cascades. 
This review synthesizes current mechanistic evidence that natural antioxidants can act as neuromodulators in 
diabetic neuropathy, affecting neuronal excitability, synaptic function, neuroimmune interactions, and nerve repair. 
We discuss major compound classes (e.g., curcuminoids, resveratrol, quercetin, EGCG, ginsenosides), their 
molecular targets (mitochondria, NADPH oxidases, Nrf2, NF-κB, MAPKs, TRP channels, voltage-gated sodium 
channels, GABAergic and glutamatergic receptors), and preclinical/clinical evidence for symptomatic and disease
modifying effects. Therapeutic insights, formulation and bioavailability challenges, safety considerations, and 
rational combination strategies are outlined. We conclude by identifying promising translational paths and 
experimental priorities to move antioxidant neuromodulators from bench to bedside in diabetic neuropathy.