PMID- 30450828 OWN - NLM STAT- MEDLINE DCOM- 20200415 LR - 20210109 IS - 1582-4934 (Electronic) IS - 1582-1838 (Print) IS - 1582-1838 (Linking) VI - 23 IP - 1 DP - 2019 Jan TI - Fibroblast growth factor 21 facilitates peripheral nerve regeneration through suppressing oxidative damage and autophagic cell death. PG - 497-511 LID - 10.1111/jcmm.13952 [doi] AB - 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. CI - (c) 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. FAU - Lu, Yingfeng AU - Lu Y AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Li, Rui AU - Li R AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Zhu, Junyi AU - Zhu J AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Wu, Yanqing AU - Wu Y AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Li, Duohui AU - Li D AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Dong, Lupeng AU - Dong L AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Li, Yiyang AU - Li Y AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Wen, Xin AU - Wen X AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Yu, Fangzheng AU - Yu F AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Zhang, Hongyu AU - Zhang H AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Ni, Xiao AU - Ni X AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Du, Shenghu AU - Du S AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Li, Xiaokun AU - Li X AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xiao, Jian AU - Xiao J AUID- ORCID: 0000-0001-8317-621X AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Wang, Jian AU - Wang J AD - Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181118 PL - England TA - J Cell Mol Med JT - Journal of cellular and molecular medicine JID - 101083777 RN - 0 (Antioxidants) RN - 0 (NF-E2-Related Factor 2) RN - 0 (fibroblast growth factor 21) RN - 62031-54-3 (Fibroblast Growth Factors) SB - IM MH - Animals MH - Antioxidants/metabolism MH - Autophagic Cell Death/*physiology MH - Axons/metabolism/physiology MH - Cell Proliferation/physiology MH - Cells, Cultured MH - Fibroblast Growth Factors/*metabolism MH - Male MH - NF-E2-Related Factor 2/metabolism MH - Nerve Regeneration/*physiology MH - Oxidative Stress/*physiology MH - Peripheral Nerve Injuries/metabolism MH - Peripheral Nerves/*metabolism/physiology MH - Rats MH - Rats, Sprague-Dawley MH - Remyelination/physiology MH - Schwann Cells/metabolism/physiology MH - Sciatic Nerve/injuries/metabolism/physiology MH - Signal Transduction/physiology PMC - PMC6307793 OTO - NOTNLM OT - autophagic cell death OT - fibroblast growth factor 21 OT - oxidative stress OT - peripheral nerve injury OT - remyelination EDAT- 2018/11/20 06:00 MHDA- 2020/04/16 06:00 PMCR- 2019/01/01 CRDT- 2018/11/20 06:00 PHST- 2018/05/22 00:00 [received] PHST- 2018/09/12 00:00 [accepted] PHST- 2018/11/20 06:00 [pubmed] PHST- 2020/04/16 06:00 [medline] PHST- 2018/11/20 06:00 [entrez] PHST- 2019/01/01 00:00 [pmc-release] AID - JCMM13952 [pii] AID - 10.1111/jcmm.13952 [doi] PST - ppublish SO - J Cell Mol Med. 2019 Jan;23(1):497-511. doi: 10.1111/jcmm.13952. Epub 2018 Nov 18.