Acidic fibroblast growth factor attenuates type 2 diabetes-induced demyelination via suppressing oxidative stress damage

Rui Li,Yanqing Wu,Yuan Yuan,Hongyu Zhang,Libing Ye,Luxia Ye,Beini Wang,Jian Wang,Chengbiao Wu,Xiongjian Chen,Xiaokun Li,Duohui Li,Ling Xie,Jian Xiao,Peifeng Li

doi:10.1038/s41419-021-03407-2

Rui Li, Yanqing Wu + Show 13 more

Open Access

https://doi.org/10.1038/s41419-021-03407-2

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Abstract

Prolonged type 2 diabetes mellitus (T2DM) produces a common complication, peripheral neuropathy, which is accompanied by nerve fiber disorder, axon atrophy, and demyelination. Growing evidence has characterized the beneficial effects of acidic fibroblast growth factor (aFGF) and shown that it relieves hyperglycemia, increases insulin sensitivity, and ameliorates neuropathic impairment. However, there is scarce evidence on the role of aFGF on remodeling of aberrant myelin under hyperglycemia condition. Presently, we observed that the expression of aFGF was rapidly decreased in a db/db T2DM mouse model. Administration of exogenous aFGF was sufficient to block acute demyelination and nerve fiber disorganization. Furthermore, this strong anti-demyelinating effect was most likely dominated by an aFGF-mediated increase of Schwann cell (SC) proliferation and migration as well as suppression of its apoptosis. Mechanistically, the beneficial biological effects of aFGF on SC behavior and abnormal myelin morphology were likely due to the inhibition of hyperglycemia-induced oxidative stress activation, which was most likely activated by kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived-like 2 (Nrf2) signaling. Thus, this evidence indicates that aFGF is a promising protective agent for relieving myelin pathology through countering oxidative stress signaling cascades under diabetic conditions.

Highlights

Introduction Type2 diabetes mellitus (T2DM), a clinical chronic disease worldwide, has become an epidemic disease accompanying insulin resistance and insulin secretion defect[1,2]
Our findings indicated that acidic fibroblast growth factor (aFGF) ameliorates demyelination and upregulates myelin-related proteins and genes in chronic type 2 diabetes mellitus (T2DM), and these effects were likely regulated by facilitating Schwann cell (SC) proliferation and migration and inhibiting its apoptosis
We found that the fluorescence intensity for aFGF was nearly colocalized with that for S100, suggesting that aFGF is mainly expressed in SCs (Fig. 1c and d)

Summary

Introduction

2 diabetes mellitus (T2DM), a clinical chronic disease worldwide, has become an epidemic disease accompanying insulin resistance and insulin secretion defect[1,2]. Long-term hyperglycemia in the peripheral nervous system (PNS) causes nerve damage and cytotoxicity, which leads to myelin sheath vacuolar degeneration and the generation of numerous onion bulb-shaped formations. If these pathological changes continue throughout T2DM progression, the impaired nerve fibers undergo segmental demyelination, eventually leading to diabetic peripheral neuropathy (DPN). Experimental and clinical studies have demonstrated that patients with demyelinating neuropathy have a higher risk of developing sensory deficits and muscle weakness, as well as foot ulceration[6,7,8,9]. Preventing demyelination progression in T2DM is a critical issue for ameliorating abnormal nerve function

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