PMID- 31998447 OWN - NLM STAT- MEDLINE DCOM- 20200603 LR - 20200603 IS - 1942-0994 (Electronic) IS - 1942-0900 (Print) IS - 1942-0994 (Linking) VI - 2020 DP - 2020 TI - Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule. PG - 9741369 LID - 10.1155/2020/9741369 [doi] LID - 9741369 AB - Spinal cord injury (SCI) is a devastating disease that may lead to lifelong disability. Thus, seeking for valid drugs that are beneficial to promoting axonal regrowth and elongation after SCI has gained wide attention. Metformin, a glucose-lowering agent, has been demonstrated to play roles in various central nervous system (CNS) disorders. However, the potential protective effect of metformin on nerve regeneration after SCI is still unclear. In this study, we found that the administration of metformin improved functional recovery after SCI through reducing neuronal cell apoptosis and repairing neurites by stabilizing microtubules via PI3K/Akt signaling pathway. Inhibiting the PI3K/Akt pathway with LY294002 partly reversed the therapeutic effects of metformin on SCI in vitro and vivo. Furthermore, metformin treatment weakened the excessive activation of oxidative stress and improved the mitochondrial function by activating the nuclear factor erythroid-related factor 2 (Nrf2) transcription and binding to the antioxidant response element (ARE). Moreover, treatment with Nrf2 inhibitor ML385 partially abolished its antioxidant effect. We also found that the Nrf2 transcription was partially reduced by LY294002 in vitro. Taken together, these results revealed that the role of metformin in nerve regeneration after SCI was probably related to stabilization of microtubules and inhibition of the excessive activation of Akt-mediated Nrf2/ARE pathway-regulated oxidative stress and mitochondrial dysfunction. Overall, our present study suggests that metformin administration may provide a potential therapy for SCI. CI - Copyright (c) 2020 Haoli Wang et al. FAU - Wang, Haoli AU - Wang H AUID- ORCID: 0000-0003-0694-2341 AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Zheng, Zhilong AU - Zheng Z AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Han, Wen AU - Han W AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Yuan, Yuan AU - Yuan Y AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Li, Yao AU - Li Y AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Zhou, Kailiang AU - Zhou K AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Wang, Qingqing AU - Wang Q AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xie, Ling AU - Xie L AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xu, Ke AU - Xu K AD - The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, Zhejiang, China 325035. FAU - Zhang, Hongyu AU - Zhang H AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xu, Huazi AU - Xu H AD - Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Wu, Yanqing AU - Wu Y AUID- ORCID: 0000-0001-6535-6655 AD - The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, Zhejiang, China 325035. FAU - Xiao, Jian AU - Xiao J AUID- ORCID: 0000-0001-7374-6506 AD - Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. LA - eng PT - Journal Article DEP - 20200106 PL - United States TA - Oxid Med Cell Longev JT - Oxidative medicine and cellular longevity JID - 101479826 RN - 0 (Chromones) RN - 0 (Morpholines) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, rat) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Axons/*physiology MH - Chromones/pharmacology MH - Metformin/*pharmacology MH - *Microtubules/metabolism/pathology MH - Mitochondria/metabolism/pathology MH - Morpholines/pharmacology MH - NF-E2-Related Factor 2/metabolism MH - Oxidative Stress/*drug effects MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Regeneration/*drug effects MH - Response Elements MH - *Spinal Cord Injuries/drug therapy/metabolism/pathology PMC - PMC6969994 COIS- The authors confirm that there are no conflicts of interest. EDAT- 2020/01/31 06:00 MHDA- 2020/06/04 06:00 PMCR- 2020/01/06 CRDT- 2020/01/31 06:00 PHST- 2019/03/26 00:00 [received] PHST- 2019/11/07 00:00 [revised] PHST- 2019/11/13 00:00 [accepted] PHST- 2020/01/31 06:00 [entrez] PHST- 2020/01/31 06:00 [pubmed] PHST- 2020/06/04 06:00 [medline] PHST- 2020/01/06 00:00 [pmc-release] AID - 10.1155/2020/9741369 [doi] PST - epublish SO - Oxid Med Cell Longev. 2020 Jan 6;2020:9741369. doi: 10.1155/2020/9741369. eCollection 2020.