Skip to main content

Advertisement

Log in

Exercise inhibits neuronal apoptosis and improves cerebral function following rat traumatic brain injury

  • Basic Neurosciences, Genetics and Immunology - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Exercise is reported to inhibit neuronal apoptotic cell death in the hippocampus and improve learning and memory. However, the effect of exercise on inhibition of neuronal apoptosis surrounding the area of damage after traumatic brain injury (TBI) and the improvement of cerebral dysfunction following TBI are unknown. Here, we investigate the effect of exercise on morphology and cerebral function following TBI in rats. Wistar rats received TBI by a pneumatic controlled injury device were randomly divided into two groups: (1) non-exercise group and (2) exercise group. The exercise group ran on a treadmill for 30 min/day at 22 m/min for seven consecutive days. Immunohistochemical and behavioral studies were performed following TBI. The number of single-stranded DNA (ssDNA)-positive cells around the damaged area early after TBI was significantly reduced in the exercise group compared with the non-exercise group (P < 0.05). Furthermore, most ssDNA-positive cells in the non-exercise group co-localized with neuronal cells. However, in the exercise group, a few ssDNA-positive cells co-localized with neurons. In addition, there was a significant increase in neuronal cell number and improvement in cerebral dysfunction after TBI in the exercise group compared with the non-exercise group (P < 0.05). These results indicate that exercise following TBI inhibits neuronal degeneration and apoptotic cell death around the damaged area, which results in improvement of cerebral dysfunction. In summary, treadmill running improved cerebral dysfunction following TBI, indicating its potential as an effective clinical therapy. Therefore, exercise therapy (rehabilitation) in the early phase following TBI is important for recuperation from cerebral dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Azbill RD, Mu X, Bruce-Keller AJ, Mattson MP, Springer JE (1997) Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury. Brain Res 765:283–290

    Article  PubMed  CAS  Google Scholar 

  • Blackmore DG, Golmohammadi MG, Large B, Waters MJ, Rietze RL (2009) Exercise increases neural stem cell number in a growth hormone-dependent manner, augmenting the regenerative response in aged mice. Stem Cells 27:2044–2052

    Article  PubMed  CAS  Google Scholar 

  • Cechetti F, Fochesatto C, Scopel D, Nardin P, Goncalves CA, Netto CA, Siqueira IR (2008) Effect of a neuroprotective exercise protocol on oxidative state and BDNF levels in the rat hippocampus. Brain Res 1188:182–188

    Article  PubMed  CAS  Google Scholar 

  • Chae CH, Kim HT (2009) Forced, moderate-intensity treadmill exercise suppresses apoptosis by increasing the level of NGF and stimulating phosphatidylinositol 3-kinase signaling in the hippocampus of induced aging rats. Neurochem Int 55:208–213

    Article  PubMed  CAS  Google Scholar 

  • Chan PH, Fishman RA, Longar S, Chen S, Yu A (1985) Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury. Prog Brain Res 63:227–235

    Article  PubMed  CAS  Google Scholar 

  • Chirumamilla S, Sun D, Bullock MR, Colello RJ (2002) Traumatic brain injury induced cell proliferation in the adult mammalian central nervous system. J Neurotrauma 19:693–703

    Article  PubMed  CAS  Google Scholar 

  • Clausen F, Lundqvist H, Ekmark S, Lewen A, Ebendal T, Hillered L (2004) Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. J Neurotrauma 21:1168–1182

    Article  PubMed  Google Scholar 

  • Dressler J, Vemuganti R (2009) Apoptosis and gene expression after TBI. Leg Med (Tokyo) 11(Suppl 1): S54–S55

    Google Scholar 

  • Hall ED, Braughler JM (1989) Central nervous system trauma and stroke II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic Biol Med 6:303–313

    Article  PubMed  CAS  Google Scholar 

  • Hata R, Gillardon F, Michaelidis TM, Hossmann KA (1999) Targeted disruption of the bcl-2 gene in mice exacerbates focal ischemic brain injury. Metab Brain Dis 14:117–124

    Article  PubMed  CAS  Google Scholar 

  • Hayes K, Sprague S, Guo M, Davis W, Friedman A, Kumar A, Jimenez DF, Ding Y (2008) Forced, not voluntary, exercise effectively induces neuroprotection in stroke. Acta Neuropathol 115:289–296

    Article  PubMed  CAS  Google Scholar 

  • Hennigan A, O’Callaghan RM, Kelly AM (2007) Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection. Biochem Soc Trans 35:424–427

    Article  PubMed  CAS  Google Scholar 

  • Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336

    Article  PubMed  CAS  Google Scholar 

  • Hsuan SL, Klintworth HM, Xia Z (2006) Basic fibroblast growth factor protects against rotenone-induced dopaminergic cell death through activation of extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase pathways. J Neurosci 26:4481–4491

    Article  PubMed  CAS  Google Scholar 

  • Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631–647

    Article  PubMed  CAS  Google Scholar 

  • Itoh T, Satou T, Hashimoto S, Ito H (2005) Isolation of neural stem cells from damaged rat cerebral cortex after TBI. Neuroreport 16:1687–1691

    Article  PubMed  Google Scholar 

  • Itoh T, Satou T, Hashimoto S, Ito H (2007) Immature and mature neurons coexist among glial scars after rat traumatic brain injury. Neurol Res 29:734–742

    Article  PubMed  CAS  Google Scholar 

  • Itoh T, Satou T, Nishida S, Tsubaki M, Hashimoto S, Ito H (2009) Improvement of cerebral function by anti-amyloid precursor protein antibody infusion after traumatic brain injury in rats. Mol Cell Biochem 324:191–199

    Article  PubMed  CAS  Google Scholar 

  • Itoh T, Satou T, Nishida S, Tsubaki M, Imano M, Hashimoto S, Ito H (2010) Edaravone protects against apoptotic neuronal cell death and improves cerebral function after traumatic brain injury in rats. Neurochem Res 35:348–355

    Article  PubMed  CAS  Google Scholar 

  • Itoh T, Imano M, Nishida S, Tsubaki M, Hashimoto S, Ito A, Satou T (2011) Exercise increases neural stem cell proliferation surrounding the area of damage following rat traumatic brain injury. J Neural Trans 118:193–202

    Article  Google Scholar 

  • Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP (1995) Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids. Brain Res 674:196–204

    Article  PubMed  CAS  Google Scholar 

  • Kim DH, Zhao X, Tu CH, Casaccia-Bonnefil P, Chao MV (2004) Prevention of apoptotic but not necrotic cell death following neuronal injury by neurotrophins signaling through the tyrosine kinase receptor. J Neurosurg 100:79–87

    Article  PubMed  CAS  Google Scholar 

  • Lee EJ, Lee MY, Chen HY, Hsu YS, Wu TS, Chen ST, Chang GL (2005) Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J Pineal Res 38:42–52

    Article  PubMed  CAS  Google Scholar 

  • Liebelt B, Papapetrou P, Ali A, Guo M, Ji X, Peng C, Rogers R, Curry A, Jimenez D, Ding Y (2010) Exercise preconditioning reduces neuronal apoptosis in stroke by up-regulating heat shock protein-70 (heat shock protein-72) and extracellular-signal-regulated-kinase 1/2. Neuroscience 166:1091–1100

    Article  PubMed  CAS  Google Scholar 

  • Llorens-Martin M, Torres-Aleman I, Trejo JL (2010) Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour. Mol Cell Neurosci 44:109–117

    Article  PubMed  CAS  Google Scholar 

  • Lyden P, Wahlgren NG (2000) Mechanisms of action of neuroprotectants in stroke. J Stroke Cerebrovasc Dis 9:9–14

    Article  PubMed  CAS  Google Scholar 

  • Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, Pietra C et al (1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030

    Article  PubMed  CAS  Google Scholar 

  • McGraw J, Hiebert GW, Steeves JD (2001) Modulating astrogliosis after neurotrauma. J Neurosci Res 63:109–115

    Article  PubMed  CAS  Google Scholar 

  • Nguyen TL, Kim CK, Cho JH, Lee KH, Ahn JY (2010) Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19–7 cells. Exp Mol Med 42:583–595

    Article  PubMed  CAS  Google Scholar 

  • Radak Z, Kaneko T, Tahara S, Nakamoto H, Pucsok J, Sasvari M, Nyakas C, Goto S (2001) Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem Int 38:17–23

    Article  PubMed  CAS  Google Scholar 

  • Rice AC, Khaldi A, Harvey HB, Salman NJ, White F, Fillmore H, Bullock MR (2003) Proliferation and neuronal differentiation of mitotically active cells following traumatic brain injury. Exp Neurol 183:406–417

    Article  PubMed  CAS  Google Scholar 

  • Rizk NN, Myatt-Jones J, Rafols J, Dunbar JC (2007) Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine 31:66–71

    Article  PubMed  CAS  Google Scholar 

  • Sahin S, Alkan T, Temel SG, Tureyen K, Tolunay S, Korfali E (2010) Effects of citicoline used alone and in combination with mild hypothermia on apoptosis induced by focal cerebral ischemia in rats. J Clin Neurosci 17:227–231

    Article  PubMed  CAS  Google Scholar 

  • Shin DH, Lee E, Kim JW, Kwon BS, Jung MK, Jee YH, Kim J, Bae SR, Chang YP (2004) Protective effect of growth hormone on neuronal apoptosis after hypoxia-ischemia in the neonatal rat brain. Neurosci Lett 354:64–68

    Article  PubMed  CAS  Google Scholar 

  • Sim YJ, Kim H, Kim JY, Yoon SJ, Kim SS, Chang HK, Lee TH, Lee HH, Shin MC, Shin MS, Kim CJ (2005) Long-term treadmill exercise overcomes ischemia-induced apoptotic neuronal cell death in gerbils. Physiol Behav 84:733–738

    Article  PubMed  CAS  Google Scholar 

  • Sugawara T, Noshita N, Lewen A, Gasche Y, Ferrand-Drake M, Fujimura M, Morita-Fujimura Y, Chan PH (2002) Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation. J Neurosci 22:209–217

    PubMed  CAS  Google Scholar 

  • Sun X, Huang L, Zhang M, Sun S, Wu Y (2010) Insulin like growth factor-1 prevents 1-mentyl-4-phenylphyridinium-induced apoptosis in PC12 cells through activation of glycogen synthase kinase-3beta. Toxicology 271:5–12

    Article  PubMed  CAS  Google Scholar 

  • Uda M, Ishido M, Kami K, Masuhara M (2006) Effects of chronic treadmill running on neurogenesis in the dentate gyrus of the hippocampus of adult rat. Brain Res 1104:64–72

    Article  PubMed  CAS  Google Scholar 

  • Uysal N, Tugyan K, Kayatekin BM, Acikgoz O, Bagriyanik HA, Gonenc S, Ozdemir D, Aksu I, Topcu A, Semin I (2005) The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory. Neurosci Lett 383:241–245

    Article  PubMed  CAS  Google Scholar 

  • Wei OY, Huang YL, Da CD, Cheng JS (2000) Alteration of basic fibroblast growth factor expression in rat during cerebral ischemia. Acta Pharmacol Sin 21:296–300

    PubMed  CAS  Google Scholar 

  • Wine RN, McPherson CA, Harry GJ (2009) IGF-1 and pAKT signaling promote hippocampal CA1 neuronal survival following injury to dentate granule cells. Neurotox Res 16:280–292

    Article  PubMed  CAS  Google Scholar 

  • Wu CW, Chen YC, Yu L, Chen HI, Jen CJ, Huang AM, Tsai HJ, Chang YT, Kuo YM (2007) Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory. J Neurochem 103:2471–2481

    Article  PubMed  CAS  Google Scholar 

  • Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP (1997) Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23–34

    Article  PubMed  CAS  Google Scholar 

  • Xiong Y, Mahmood A, Lu D, Qu C, Kazmi H, Goussev A, Zhang ZG, Noguchi CT, Schallert T, Chopp M (2008) Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system. Brain Res 1230:247–257

    Article  PubMed  CAS  Google Scholar 

  • Yi SS, Hwang IK, Yoo KY, Park OK, Yu J, Yan B, Kim IY, Kim YN, Pai T, Song W, Lee IS, Won MH, Seong JK, Yoon YS (2009) Effects of treadmill exercise on cell proliferation and differentiation in the subgranular zone of the dentate gyrus in a rat model of type II diabetes. Neurochem Res 34:1039–1046

    Article  PubMed  CAS  Google Scholar 

  • Zhang C, Shen W, Zhang G (2002) N-methyl-D-aspartate receptor and L-type voltage-gated Ca(2+) channel antagonists suppress the release of cytochrome c and the expression of procaspase-3 in rat hippocampus after global brain ischemia. Neurosci Lett 328:265–268

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research (20500472 and 21500803) and ZENRYOKEN. The authors thank Mari Yachi for technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tatsuki Itoh.

Additional information

Grant information

(1) Grants-in-Aid for Scientific Research, numbers 20500472 and 21500803. (2) ZENRYOKEN.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Itoh, T., Imano, M., Nishida, S. et al. Exercise inhibits neuronal apoptosis and improves cerebral function following rat traumatic brain injury. J Neural Transm 118, 1263–1272 (2011). https://doi.org/10.1007/s00702-011-0629-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-011-0629-2

Keywords

Navigation