title: The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury.
abstract: OBJECTIVE
  To study the effect of simvastatin on neurological functional recovery after traumatic brain injuries (TBI) and the possible molecular mechanisms, we evaluated simvastatin-induced proliferation and differentiation of neural stem cells (NSCs) in vitro and in vivo and possible involvement of Notch-1 signaling in this process.
  
  
  METHODS
  Adult Wistar rats were randomly divided into three groups (n=28 for each): sham group, saline-treated group and simvastatin-treated group. Simvastatin was given orally at a dose of 1mg/kg/day starting at day 1 after TBI. At 1, 3, 7, 14, 21, 28, and 35 days after simvastatin treatment, functional outcome was measured using modified neurological severity scores (mNSS). Immunofluorescence of nestin was used to identify neurogenesis of NSCs in injured area of TBI rats. Western blot was applied to detect the expression level of Notch-1 protein in TBI rats with simvastatin.
  
  
  RESULTS
  Immunostaining showed a significant increase in the number of nestin-positive cells in injured area of the simvastatin-treated group compared to that of the saline-treated group (p<0.05). In in vitro experiment, simvastatin induced enhanced proliferation and neurogenesis of cultured NSCs and elevated Notch-1 protein expression. Co-incubation of γ-secretase inhibitor, an inhibitor of Notch-1 pathway, with simvastatin abolished its neurorestoration effect. Most importantly, the simvastatin-treated group had significantly decreased mNSS at day 35 after TBI compared with the saline-treated group (p<0.05).
  
  
  CONCLUSIONS
  Simvastatin treatment enhanced neurological functional recovery after TBI possibly via activation of Notch signaling and increasing neurogenesis in the injured area.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Chuncheng
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Damin
authors.initials: D
authors.lastname: Cong
authors.affiliation: Department of pediatric, The Heilongjiang Province Hospital, Harbin, Heilongjiang, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. Electronic address: zgxgtg@sina.com.
authors.forename: Xiangtong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008297:Male; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C577486:Nes protein, rat; D064231:Nestin; D018696:Neuroprotective Agents; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D019821:Simvastatin; D053829:Amyloid Precursor Protein Secretases
keywords: Neural stem cells; Notch signaling; Simvastatin; Traumatic brain injury