Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy

Abstract

Background/Aims: High glucose-induced oxidative stress and inflammatory responses play an important role in painful diabetic neuropathy by activating the TLR4/NFκB signal pathway. Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs provide a microenvironment favoring vascular regeneration but their low survival ratio in hyperglycemic conditions suppress the function to promote nerve growth. Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes remyelination after peripheral nerve injury. The aim of this study was to identify the role of Nrf2 in SC-mediated functional recovery after sciatic nerve injury. Methods: We compared plasma inflammatory factors in diabetic patients (DN) with/without diabetic peripheral neuropathy (DPN) and assessed whether Nrf2 expression in SCs could repair peripheral nerve injury in a rat model. Nrf2, TLR4/NFκB signal pathway and apoptosis relative protein expression were detected by western blot. Apoptosis and angiogenesis were determined by immunofluorescence and tubule formation assay, respectively. Regenerated nerves were determined by transmission electron microscope. Results: Higher levels of inflammatory factors and VEGF expression were found in DPN patients. Cellular experiments indicate that Nrf2 expression inhibits hyperglycemia-induced apoptosis and promotes angiogenesis by regulating the TLR4/NFκB signal pathway. Animal experiments show that nerve conduction velocity, myelin sheath thickness, and sciatic vasa nervorum are restored with transplantation of SCs overexpressing Nrf2. Conclusions: Taken together, the high survival ratio of SCs in a DPN rat model indicates that overexpression of Nrf2 restores nerve injury.

Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-κB signaling pathways

“…Meanwhile, a previous study verified that Nrf2 expression inhibits hyperglycemia-induced peripheral nerve injury by suppressing the TLR4/NF-κB signaling pathway [ 50 ]. The expression of Nrf2 also suppresses TLR4/NF-κB-mediated inflammatory cytokine expression [ 51 , 52 ].…”

Omega‐3 polyunsaturated fatty acids exert anti‐oxidant effects through the nuclear factor (erythroid‐derived 2)‐related factor 2 pathway in immortalized mouse Schwann cells

“…Nrf2 pathway activation initiates the transcriptional regulation of ARE‐dependent expression of diverse anti‐oxidants and phase II detoxification enzymes, including heme oxygenase‐1 (Ho‐1) and nicotinamide adenine dinucleotide (phosphate) H quinone oxidoreductase 1 (Nqo1). Furthermore, the overexpression of Nrf2 reportedly inhibits apoptosis that is induced by high glucose in Schwann cells, and the transplantation of Nrf2‐overexpressing Schwann cells can recover nerve functions in diabetic animals. Therefore, Nrf2 has become a therapeutic target in diabetic peripheral neuropathy.…”

The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain

“…The vascular complications of diabetic neuropathy involve impaired endoneurial blood flow to the peripheral nerves, leading to the destruction of neurons and Schwann cells (SCs) [ 58 ]. Overexpression of Nrf2 may repair nerve injury as Tang et al reported that SCs overexpressing Nrf2 restored nerve conduction velocity, myelin sheath thickness, and sciatic vasa nervorum while also inhibiting hyperglycemia-induced apoptosis [ 59 ]. Further, overexpressing Nrf2 promoted angiogenesis by regulating the Toll-like receptor 4/NF-κB signaling pathway in a rodent model of diabetic neuropathy [ 59 ].…”