title: Etifoxine promotes glia-derived neurite outgrowth in vitro and in vivo.
abstract: BACKGROUND
  Peripheral nerve injuries usually require a graft to facilitate axonal regeneration into the distal nerve stump. Acellular nerve grafts are good candidates for nerve repair, but clinical outcomes from grafts are not always satisfactory. Etifoxine is a ligand of the 18-kDa translocator protein (TSPO) and has been demonstrated to serve multiple functions in nervous system.
  
  
  METHODS
  This study aimed to determine the optimal concentration of etifoxine for neurite outgrowth using PC12 cells and verify whether etifoxine could enhance in vivo peripheral nerve regeneration. PC12 cells were exposed to various concentrations of etifoxine (5, 10, 20, and 40 µM). Neuronal-like outgrowth and glia-derived neurotrophic factor (GDNF) mRNA expression were measured, and a rat sciatic nerve transection model was employed. Histological examination was used to evaluate the efficacy of nerve regeneration, and real-time polymerase chain reaction (PCR) evaluated changes in mRNA levels after etifoxine treatment.
  
  
  RESULTS
  Our data show that etifoxine increased neuronal-like outgrowth in PC12 cells in a dose-dependent manner; however, GDNF expression peaked at 20 µM etifoxine (1.97-fold increase compared with control, p = 0.0046). In vivo studies demonstrated that etifoxine improved sciatic nerve regeneration, modulated immune responses, and boosted neurotrophin expression.
  
  
  CONCLUSIONS
  Because of etifoxine's adverse effects, we suggest an optimal etifoxine concentration of 20 µM. Its beneficial role may lie in increased neurotrophin expression, and etifoxine may be a promising therapeutic for patients with peripheral nerve injuries.
authors: Department of Biotechnology, School of Basic Science, Guangzhou Medical University, Guangzhou, China.
authors: Ting
authors: T
authors: Dai
authors: Department of Microsurgery and Orthopaedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Xiang
authors: X
authors: Zhou
authors: Department of Biochemistry & Molecular Biology, School of Basic Science, Guangzhou Medical University, Guangzhou, China.
authors: Yanan
authors: Y
authors: Li
authors: Department of Microsurgery and Orthopaedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Bo
authors: B
authors: He
authors: Department of Microsurgery and Orthopaedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Zhaowei
authors: Z
authors: Zhu
authors: Department of Microsurgery and Orthopaedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Canbin
authors: C
authors: Zheng
authors: Department of Microsurgery and Orthopaedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Shuang
authors: S
authors: Zhu
authors: Department of Microsurgery and Orthopaedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Qingtang
authors: Q
authors: Zhu
authors: Department of Microsurgery and Orthopaedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors: Xiaolin
authors: X
authors: Liu
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D010078:Oxazines / Q000008:administration & dosage*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000293:injuries / Q000601:surgery* / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D007375:Interleukin-1; D009414:Nerve Growth Factors; D010078:Oxazines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C002125:etifoxine