Fibroblast growth factor 21 facilitates peripheral nerve regeneration through suppressing oxidative damage and autophagic cell death

Abstract

Seeking for effective drugs which are beneficial to facilitating axonal regrowth and elongation after peripheral nerve injury (PNI) has gained extensive attention. Fibroblast growth factor 21 (FGF21) is a metabolic factor that regulates blood glucose and lipid homeostasis. However, there is little concern for the potential protective effect of FGF21 on nerve regeneration after PNI and revealing related molecular mechanisms. Here, we firstly found that exogenous FGF21 administration remarkably promoted functional and morphologic recovery in a rat model of sciatic crush injury, manifesting as persistently improved motor and sensory function, enhanced axonal remyelination and regrowth and accelerated Schwann cells (SCs) proliferation. Furthermore, local FGF21 application attenuated the excessive activation of oxidative stress, which was accompanied with the activation of nuclear factor erythroid‐2‐related factor 2 (Nrf‐2) transcription and extracellular regulated protein kinases (ERK) phosphorylation. We detected FGF21 also suppressed autophagic cell death in SCs. Additionally, treatment with the ERK inhibitor U0126 or autophagy inhibitor 3‐MA partially abolishes anti‐oxidant effect and reduces SCs death. Taken together, these results indicated that the role of FGF21 in remyelination and nerve regeneration after PNI was probably related to inhibit the excessive activation of ERK/Nrf‐2 signalling‐regulated oxidative stress and autophagy‐induced cell death. Overall, our work suggests that FGF21 administration may provide a new therapy for PNI.

SIRT1 Mediates Effects of FGF21 to Ameliorate Cisplatin-Induced Acute Kidney Injury

“…Many studies have previously shown that loss of FGF21 causes pathologic damage in multiple animal models, including decreased productivity of pancreatic beta cells and insulin sensitivity (Lee et al, 2018;Wanders et al, 2017), promotion of the development of fatty liver in mice followed by aggravation of liver fibrosis (Singhal et al, 2018), and even aggravation of cisplatin-induced AKI (Holditch et al, 2019). Similarly, overexpression of FGF21 or administration of exogenous FGF21 regulates metabolism, controls the stress response, and attenuates organ damage (So and Leung, 2016;Kang et al, 2018;Lu et al, 2019;Suassuna et al, 2019). Our results are consistent with previous reports.…”

“…Previous studies showed that serum levels of FGF21 are significantly increased in both AKI and CKD, and FGF21 concentration is correlated with the severity of kidney injury (Li F. et al, 2018;Suassuna et al, 2019). However, numerous studies have demonstrated that FGF21 functions in alleviating inflammation and in the regulation of oxidative stress and autophagy-induced apoptosis (Lu et al, 2019;Suassuna et al, 2019). Recent works also showed that FGF21 significantly reduces urinary albumin levels in type II diabetic mice and alleviates kidney injury (So and Leung, 2016;Zhao et al, 2017).…”

Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule

“…In this study, we found that metformin enhanced the number of Nissl bodies and maintained their normal morphology by activating the PI3K/Akt pathway, indicating that metformin treatment can protect neurons from SCI-induced apoptosis through the PI3K/Akt signaling pathway. In addition, Lu et al had verified that fibroblast growth factor 21 improved functional recovery and axonal regeneration through regulating oxidative stress after PNI [59]. Reducing excessive oxidative stress improves the locomotor functional recovery after SCI [60].…”

Effects of Resistance Training and Bowdichia virgilioides Hydroethanolic Extract on Oxidative Stress Markers in Rats Submitted to Peripheral Nerve Injury

“…Damage to nerve endings promoted by PNI leads to the disuse of the skeletal muscle innervated by the injured branch [ 15 ]. Therefore, ischemic and inflammatory processes are involved, resulting in the emergence of oxidative stress (OS) [ 15 , 16 ].…”

“…Damage to nerve endings promoted by PNI leads to the disuse of the skeletal muscle innervated by the injured branch [ 15 ]. Therefore, ischemic and inflammatory processes are involved, resulting in the emergence of oxidative stress (OS) [ 15 , 16 ]. Once the peripheral nerve suffers damage, there is accumulation of pro-oxidant substances; simultaneously, the levels of endogenous antioxidants are insufficient to maintain resistance to oxidative damage [ 15 ].…”