Redox-Driven Blood-Nerve Barrier Dysfunction in Diabetic Peripheral Neuropathy: Mechanisms and Therapeutic Opportunities

Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic. Increasing evidence places early dysfunction of the blood-nerve barrier (BNB)—a core element of the peripheral nerve neurovascular unit (PNVU)—at the intersection of metabolic stress and neuroinflammation. This review synthesizes a redox-centered model of BNB failure in DPN: (i) chronic hyperglycemia and dyslipidemia overwhelm endogenous antioxidant defenses, driving reactive oxygen species (ROS) imbalance; (ii) ROS-associated endothelial activation promotes endothelial-immune crosstalk, leukocyte recruitment, and macrophage polarization; and (iii) progressive loss of tight-junction and barrier homeostasis increases paracellular permeability and exposure of nerves to pro-inflammatory and neurotoxic mediators. We then evaluate incretin-based therapies—GLP-1 receptor agonists, DPP-4 inhibitors, and emerging multi-agonists—as potential modulators of PNVU/BNB stress. Beyond glucose and weight effects, these agents may dampen oxidative and inflammatory signaling, engage antioxidant pathways (e.g., Nrf2), and potentially support molecular determinants of BNB integrity via indirect metabolic unloading and possible GLP-1R-dependent vascular-immune actions. By reframing DPN as a neurovascular-immune disorder driven by redox imbalance, we highlight barrier-focused biomarkers and hypothesis-generating therapeutic opportunities that require clinical validation.