What question did this study set out to answer?

May 28, 2026Open Access

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

WHWei-Hsiu HuangCathay General Hospital CWChih-Shung WongCathay General Hospital

Key Points

This review aims to explore the mechanisms of blood–nerve barrier dysfunction in diabetic peripheral neuropathy and potential therapeutic interventions.
Synthesis of clinical, redox, vascular, and immunological evidence into a framework for peripheral nerve neurovascular unit and blood–nerve barrier.
Review anatomical and functional aspects of the blood–nerve barrier including key cellular components and signaling pathways.
Evaluate incretin-based therapies as potential modulators of oxidative and inflammatory stress in this context.
Outlined the impact of chronic hyperglycemia and dyslipidemia on redox imbalance and blood–nerve barrier permeability.
Reviewed potential of incretin therapies, particularly GLP-1 receptor agonists, to modulate oxidative and inflammatory stress, though direct human evidence remains limited.
Identified barrier-focused biomarkers and translational endpoints that require further clinical validation.

Abstract

Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic and does not directly address early neurovascular-immune pathology. This narrative review synthesizes clinical, redox, vascular, and immunological evidence into a peripheral nerve neurovascular unit (PNVU)/blood–nerve barrier (BNB)-centered framework for DPN. First, the review outlines the diagnostic and translational endpoint landscape of DPN, emphasizing that commonly used clinical, neurophysiological, small-fiber, and imaging-based tools capture important disease domains but do not directly assess early BNB dysfunction. It then reviews the anatomical and functional basis of the PNVU and BNB, including endoneurial microvascular endothelial cells, pericytes, basement membrane components, immune cells, and tight-junction proteins. Next, it discusses how chronic hyperglycemia and dyslipidemia drive metabolic-to-vascular coupling, redox imbalance, antioxidant defense failure, advanced glycation end products (AGEs), receptor for AGEs (RAGE), and nuclear factor-κB (NF-κB) signaling, endothelial activation, leukocyte recruitment, macrophage polarization, and junctional disassembly, culminating in increased BNB permeability and exposure of peripheral nerves to pro-inflammatory and neurotoxic mediators. Finally, it evaluates incretin-based therapies—including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, DPP-4is), and emerging multi-agonists—as potential modulators of oxidative and inflammatory stress within this framework. Although semaglutide and related agents show mechanistic plausibility and preclinical promise, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited. By reframing DPN as a redox-driven neurovascular-immune disorder, this review highlights barrier-focused biomarkers, translational endpoints, and hypothesis-generating therapeutic opportunities that require clinical validation.

Ask AI

Helpful

Bookmark

View Full Paper