title: Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus.
abstract: The antidepressant-like effects of simvastatin on traumatic brain injury (TBI) remain unclear. The present study aimed to investigate the neuroprotective effects of simvastatin and determine whether simvastatin attenuates TBI-induced depression-like behavior and, more specifically, acts as an antineuroinflammatory.
  
  
  
  Anesthetized male Sprague-Dawley rats were divided into five groups: sham-operated controls, TBI controls, and TBI treatment with simvastatin 4, 10, or 20 mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 h after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests. Neuronal apoptosis (markers: NeuN, TUNEL, caspase-3), microglia (marker: OX42) and astrocyte (marker: GFAP) activation, and TNF-α expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay. All parameters were measured on the 4th, 8th, and 15th day, or only on the 15th day after TBI.
  
  
  
  TBI-induced depression-like behavior, which increased duration of immobility, was significantly attenuated by 20 mg simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-α expression in the microglia and astrocytes of the CA3 area of the hippocampus were significantly reduced by simvastatin treatment, particularly when 20 mg/kg was administered for 3 days.
  
  
  
  Intraperitoneal injection of simvastatin attenuated TBI in rats during the acute stage by reducing neuronal apoptosis, microglia, and TNF-α expression, thereby resulting in a reduction of depressive-like behavior. Our results suggest that simvastatin may be a promising treatment for TBI-induced depression-like behavior.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.|Department of Neurosurgery, Chi-Mei Medical Center, Chiali, Tainan, Taiwan.|Department of Nursing, Min-Hwei College of Health Care Management, Tainan, Taiwan.
authors.forename: Sher-Wei
authors.initials: SW
authors.lastname: Lim
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Yow-Ling
authors.initials: YL
authors.lastname: Shiue
authors.affiliation: Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Liao
authors.affiliation: Department of Neurosurgery, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.
authors.forename: Hsiao-Yue
authors.initials: HY
authors.lastname: Wee
authors.affiliation: Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan.|Departments of Child Care, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
authors.forename: Che-Chuan
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Chung-Ching
authors.initials: CC
authors.lastname: Chio
authors.affiliation: Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Chin-Hung
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Chiao-Ya
authors.initials: CY
authors.lastname: Hu
authors.affiliation: Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan. kuojinnrung@gmail.com.|Departments of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. kuojinnrung@gmail.com.|Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan. kuojinnrung@gmail.com.|Chi-Mei Medical Center, #901 Chung Hwa Road, Yung Kang, Tainan, Taiwan. kuojinnrung@gmail.com.
authors.forename: Jinn-Rung
authors.initials: JR
authors.lastname: Kuo
mesh_terms: D000208:Acute Disease; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000188:drug therapy*; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
keywords: Depression-like behavior; Fluid percussion injury; Forced swim; Hippocampus; Maximal angle; Microglia; Simvastatin; Tumor necrosis factor-alpha