Neurocritical Care

, Volume 26, Issue 1, pp 122–132 | Cite as

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

  • Sher-Wei Lim
  • Yow-Ling Shiue
  • Jen-Chieh Liao
  • Hsiao-Yue Wee
  • Che-Chuan Wang
  • Chung-Ching Chio
  • Chin-Hung Chang
  • Chiao-Ya Hu
  • Jinn-Rung Kuo
Translational Research



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.


Fluid percussion injury Depression-like behavior Forced swim Hippocampus Maximal angle Microglia Tumor necrosis factor-alpha Simvastatin 



The authors thank all of the researchers, especially Chio-Ya Hu, who participated in this study. Research has been funded by CHMFHR10357 grants.

Compliance with Ethical Standards

Conflict of interest

All authors report no biomedical financial interests or potential conflicts of interest.


  1. 1.
    LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155–84.CrossRefPubMedGoogle Scholar
  2. 2.
    Zaloshnja E, Miller T, Langlois JA, Selassie AW. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehabil. 2008;23:394–400.CrossRefPubMedGoogle Scholar
  3. 3.
    Alderfer BS, Arciniegas DB, Silver JM. Treatment of depression following traumatic brain injury. J Head Trauma Rehabil. 2005;20(6):544–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Hicks R, Soares H, Smith D, McIntosh T. Temporal and spatial characterization of neuronal injury following lateral fluid-percussion brain injury in the rat. Acta Neuropathol. 1996;91:236–46.CrossRefPubMedGoogle Scholar
  5. 5.
    Sato M, Chang E, Igarashi T, Noble LJ. Neuronal injury and loss after traumatic brain injury: time course and regional variability. Brain Res. 2001;917:45–54.CrossRefPubMedGoogle Scholar
  6. 6.
    Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001;2:734–44.CrossRefPubMedGoogle Scholar
  7. 7.
    Chio CC, Lin JW, Chang MW, Wang CC, Kuo JR, Yang CZ, et al. Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem. 2010;115:921–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002;8:101–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang D, Hu X. QianL, O’Callaghan JP, Hong JS. Astrogliosis in CNS pathologies: is there a role for microglia? Mol Neurobiol. 2010;41:232–41.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues AL. Depressive-like behavior induced by tumor necrosis factor-a in mice. Neuropharmacology. 2012;62:419–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10:45–65.CrossRefPubMedGoogle Scholar
  13. 13.
    Cucchiara B, Kasner SE. Use of statins in CNS disorders. J Neurol Sci. 2001;187:81–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res. 2005;97:1232–5.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Balduini W, Mazzoni E, Carloni S, De Simoni MG, Perego C, Sironi L, et al. Prophylactic but not delayed administration of simvastatin protects against long-lasting cognitive and morphological consequences of neonatal hypoxic-ischemic brain injury, reduces interleukin-1beta and tumor necrosis factor-alpha mRNA induction, and does not affect endothelial nitric oxide synthase expression. Stroke. 2003;34:2007–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Chen SF, Hung TH, Chen CC, Lin KH, Huang YN, Tsai HC, et al. Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury. Life Sci. 2007;81:288–98.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang KW, Chen HJ, Lu K, Liliang PC, Liang CL, Tsai YD, et al. Simvastatin attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. Ann Clin Lab Sci. 2014;44:145–50.PubMedGoogle Scholar
  18. 18.
    Lindberg C, Crisby M, Winblad B, Schultzberg M. Effects of statins on microglia. J Neurosci Res. 2005;82:10–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2004;19:117–25.CrossRefGoogle Scholar
  20. 20.
    Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet. 1993;24:195–202.CrossRefPubMedGoogle Scholar
  21. 21.
    McIntosh TK, Vink R, Noble L, Yamakami I, Fernyak S, Soares H, et al. Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience. 1989;28:233–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Chuang TJ, Lin KC, Chio CC, Wang CC, Chang CP, Kuo JR. Effects of secretome obtained from normoxia-preconditioned human mesenchymal stem cells in traumatic brain injury rats. J Trauma Acute Care Surg. 2012;73:1161–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Basso AM, Gallagher KB, Bratcher NA, Brioni JD, Moreland RB, Hsieh GC, et al. Antidepressant-like effect of D(2/3) receptor-, but not D(4) receptor-activation in the rat forced swim test. Neuropsychopharmacology. 2005;30:1257–68.PubMedGoogle Scholar
  24. 24.
    Hallam TM, Floyd CL, Folkerts MM, Lee LL, Gong QZ, Lyeth BG, et al. Comparison of behavioral deficits and acute neuronal degeneration in rat lateral fluid percussion and weight-drop brain injury models. J Neurotrauma. 2004;21:521–39.CrossRefPubMedGoogle Scholar
  25. 25.
    Bao YH, Bramlett HM, Atkins CM, Truettner JS, Lotocki G, Alonso OF, et al. Post-traumatic seizures exacerbate histopathological damage after fluid-percussion brain injury. J Neurotrauma. 2011;28:35–42.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Koshinaga M, Katayama Y, Fukushima M. Rapid and widespread microglial activation induced by traumatic brain injury in rat brain slices. J Neurotrauma. 2000;17:185–92.CrossRefPubMedGoogle Scholar
  27. 27.
    Mullen RJ, Buck CR, Smith AM. Neu-N, a neuronal specific nuclear protein in vertebrates. Development. 1992;116:201–11.PubMedGoogle Scholar
  28. 28.
    Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, et al. Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3 K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J Neurotrauma. 2008;25:130–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Wang H, Lynch JR, Song P, Yang HJ, Yates RB, Mace B, et al. Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury. Exp Neurol. 2007;206:59–69.CrossRefPubMedGoogle Scholar
  30. 30.
    Tsai YT, Wang CC, Kuo JR, et al. Extracellular signal-regulated kinase 1/2 is involved in a tamoxifen neuroprotective effect in a lateral fluid percussion injury rat model. J Surg Res. 2014;189:106–16.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang CC, Lin KC, Lin BS, Chio CC, Kuo JR. Resuscitation from experimental traumatic brain injury by magnolol therapy. J Surg Res. 2013;184:1045–52.CrossRefPubMedGoogle Scholar
  32. 32.
    Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology. 1988;94:147–60.CrossRefPubMedGoogle Scholar
  33. 33.
    Lim SW, Wang CC, Wang YH, Chio CC, Niu KC, Kuo JR. Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy. J Surg Res. 2013;184:1076–84.CrossRefPubMedGoogle Scholar
  34. 34.
    Chio CC, Lin MT, Chang CP. Microglial activation as a compelling target for treating acute traumatic brain injury. Curr Med Chem. 2015;22:759–70.CrossRefPubMedGoogle Scholar
  35. 35.
    Chen G, Zhang S, Shi J, Ai J, Qi M, Hang C. Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/NF-kappaB pathway. Exp Neurol. 2009;216:398–406.CrossRefPubMedGoogle Scholar
  36. 36.
    Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci. 2002;22:3251–61.PubMedGoogle Scholar
  37. 37.
    Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, et al. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma. 2007;24:1132–46.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Qu C, Lu D, Goussev A, Schallert T, Mahmood A, Chopp M. Effect of atorvastatin on spatial memory, neuronal survival, and vascular density in female rats after traumatic brain injury. J Neurosurg. 2005;103:695–701.CrossRefPubMedGoogle Scholar
  39. 39.
    Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, et al. Increase in phosphorylation of Akt and its downstream signaling targets and suppression of apoptosis by simvastatin after traumatic brain injury. J Neurosurg. 2008;109:691–8.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Chen XR, Besson VC, Beziaud T, Plotkine M, Marchand-Leroux C. Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, and simvastatin, a 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitor, on experimental traumatic brain injury. J Pharmacol Exp Ther. 2008;326:966–74.CrossRefPubMedGoogle Scholar
  41. 41.
    Laskowitz DT, Warner DS. Statins in acute brain injury: getting the cart before the horse. Neurocrit Care. 2008;8:3–5.CrossRefPubMedGoogle Scholar
  42. 42.
    Morales K, Wittink M, Datto C, DiFilippo S, Cary M, TenHave T, et al. Simvastatin causes changes in affective processes in elderly volunteers. J Am Geriatr Soc. 2006;54:70–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Chuang CS, Yang TY, Muo CH, Su HL, Sung FC, Kao CH. Hyperlipidemia, statin use and the risk of developing depression: a nationwide retrospective cohort study. Gen Hosp Psychiatry. 2014;36:497–501.CrossRefPubMedGoogle Scholar
  44. 44.
    Fang CY, Egleston BL, Gabriel KP, Stevens VJ, Kwiterovich PO Jr, Snetselaar LG, et al. Depressive symptoms and serum lipid levels in young adult women. J Behav Med. 2013;36:143–52.CrossRefPubMedGoogle Scholar
  45. 45.
    Ancelin ML, Carrière I, Boulenger JP, Malafosse A, Stewart R, Cristol JP, et al. Gender and genotype modulation of the association between lipid levels and depressive symptomatology in community-dwelling elderly (the ESPRIT study). Biol Psychiatry. 2010;68:125–32.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Sher-Wei Lim
    • 1
    • 2
    • 8
  • Yow-Ling Shiue
    • 1
  • Jen-Chieh Liao
    • 3
  • Hsiao-Yue Wee
    • 4
  • Che-Chuan Wang
    • 3
    • 5
  • Chung-Ching Chio
    • 3
  • Chin-Hung Chang
    • 3
  • Chiao-Ya Hu
    • 7
  • Jinn-Rung Kuo
    • 3
    • 6
    • 7
    • 9
  1. 1.Institute of Biomedical SciencesNational Sun Yat-sen UniversityKaohsiungTaiwan
  2. 2.Department of NeurosurgeryChi-Mei Medical CenterTainanTaiwan
  3. 3.Departments of NeurosurgeryChi-Mei Medical CenterTainanTaiwan
  4. 4.Department of NeurosurgeryChi-Mei Medical CenterTainanTaiwan
  5. 5.Departments of Child CareSouthern Taiwan University of Science and TechnologyTainanTaiwan
  6. 6.Departments of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
  7. 7.Department of Medical ResearchChi-Mei Medical CenterTainanTaiwan
  8. 8.Department of NursingMin-Hwei College of Health Care ManagementTainanTaiwan
  9. 9.Chi-Mei Medical CenterTainanTaiwan

Personalised recommendations