Oxidative stress in diabetic peripheral neuropathies: Key mechanisms and therapeutic targets

Abstract

Oxidative stress plays a central and multifaceted role in the pathogenesis of diabetic peripheral neuropathies (DPN), one of the most common and disabling complications of diabetes mellitus. Chronic hyperglycemia initiates a cascade of interrelated metabolic disturbances including activation of the polyol, hexosamine, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and advanced glycation end-product pathways (AGE), all of which converge to increase reactive oxygen species (ROS) production, disrupt mitochondrial function, and overwhelm antioxidant defenses. These mechanisms lead to axonal degeneration, Schwann cell dysfunction, vascular impairment, and ultimately, irreversible nerve damage. At present, DPN remains largely untreatable, with available therapies offering only symptomatic relief. Increasing attention has been directed toward targeting the oxidative stress response as a potential disease-modifying strategy. Among the endogenous antioxidant defense systems implicated in DPN, the nuclear factor erythroid 2–related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) signaling pathway has emerged as a key regulator of cellular redox homeostasis and a promising therapeutic target. Current research highlights several therapeutic candidates including aldose reductase inhibitors, α-lipoic acid, benfotiamine, glucagon-like peptide-1 (GLP-1) receptor agonists, Dipeptidyl peptidase 4 (DPP-4) inhibitors, and Nrf2 activators like curcumin and bardoxolone methyl, that aim to restore redox balance and mitigate neuronal injury. This review discusses the molecular underpinnings of oxidative stress in DPN and evaluates emerging antioxidant-based strategies that hold promise for preventing or slowing disease progression.