Skip to main content
Springer Nature Link
Log in

Exercise Pre-conditioning Reduces Brain Inflammation and Protects against Toxicity Induced by Traumatic Brain Injury: Behavioral and Neurochemical Approach

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

See More

Although the favorable effects of physical exercise in neurorehabilitation after traumatic brain injury (TBI) are well known, detailed pathologic and functional alterations exerted by previous physical exercise on post-traumatic cerebral inflammation have been limited. In the present study, it is showed that fluid percussion brain injury (FPI) induced motor function impairment, followed by increased plasma fluorescein extravasation and cerebral—inflammation characterized by interleukin-1β, tumor necrosis factor-α (TNF-α) increase, and decreased IL-10. In addition, myeloperoxidase (MPO) increase and Na+,K+-ATPase activity inhibition after FPI suggest that the opening of blood–brain barrier (BBB) followed by neurtrophils infiltration and cerebral inflammation may contribute to the failure of selected targets leading to secondary damage. In fact, Pearson’s correlation analysis revealed strong correlation of MPO activity increase with Na+,K+-ATPase activity inhibition in sedentary rats. Statistical analysis also revealed that previous running exercise (4 weeks) protected against FPI-induced motor function impairment and fluorescein extravasation. Previous physical training also induced IL-10 increase per se and protected against cerebral IL-1β, and TNF-α increase and IL-10 decrease induced by FPI. This protocol of physical training was effective against MPO activity increase and Na+,K+-ATPase activity inhibition after FPI. The present protection correlated with MPO activity decrease suggests that the alteration of cerebral inflammatory status profile elicited by previous physical training reduces initial damage and limits long-term secondary degeneration after TBI. This prophylactic effect may facilitate functional recovery in patients suffering from brain injury induced by TBI.

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

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

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

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  • Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53

    Article  PubMed  CAS  Google Scholar 

  • Ang ET, Gomez-Pinilla F (2007) Potential therapeutic effects of exercise to the brain. Curr Med Chem 14:2564–2571

    Article  PubMed  CAS  Google Scholar 

  • Arida RM, Scorza FA, de Lacerda AF, Gomes da Silva S, Cavalheiro EA (2007) Physical training in developing rats does not influence the kindling development in the adult life. Physiol Behav 90:629–633

    Article  PubMed  CAS  Google Scholar 

  • Baskaya MK, Rao AM, Dogan A, Donaldson D, Dempsey RJ (1997) The biphasic opening of the blood-brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci Lett 226:33–36

    Article  PubMed  CAS  Google Scholar 

  • Black PH (2003) The inflammatory response is an integral part of the stress response: implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav Immun 17:350–364

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Cederberg D, Siesjo P (2010) What has inflammation to do with traumatic brain injury? Childs Nerv Syst 26:221–226

    Article  PubMed  Google Scholar 

  • Chen Y, Swanson RA (2003) Astrocytes and brain injury. J Cereb Blood Flow Metab 23:137–149

    Article  PubMed  Google Scholar 

  • Chow JW, Yablon SA, Horn TS, Stokic DS (2010) Temporospatial characteristics of gait in patients with lower limb muscle hypertonia after traumatic brain injury. Brain Inj 24:1575–1584

    Article  PubMed  Google Scholar 

  • Costa T, Constantino LC, Mendonca BP, Pereira JG, Herculano B, Tasca CI, Boeck CR (2010) N-methyl-d-aspartate preconditioning improves short-term motor deficits outcome after mild traumatic brain injury in mice. J Neurosci Res 88:1329–1337

    PubMed  CAS  Google Scholar 

  • Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T (1999) IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function. J Neuroimmunol 101:211–221

    Article  PubMed  CAS  Google Scholar 

  • D’Ambrosio R, Maris DO, Grady MS, Winn HR, Janigro D (1999) Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia. J Neurosci 19:8152–8162

    PubMed  Google Scholar 

  • D’Ambrosio R, Fairbanks JP, Fender JS, Born DE, Doyle DL, Miller JW (2004) Post-traumatic epilepsy following fluid percussion injury in the rat. Brain 127:304–314

    Article  PubMed  Google Scholar 

  • Ding YH, Mrizek M, Lai Q, Wu Y, Reyes R Jr, Li J, Davis WW, Ding Y (2006) Exercise preconditioning reduces brain damage and inhibits TNF-alpha receptor expression after hypoxia/reoxygenation: an in vivo and in vitro study. Curr Neurovasc Res 3:263–271

    Article  PubMed  CAS  Google Scholar 

  • Dishman RK, Armstrong RB, Delp MD, Graham RE, Dunn AL (1988) Open-field behavior is not related to treadmill performance in exercising rats. Physiol Behav 43:541–546

    Article  PubMed  CAS  Google Scholar 

  • Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL (1991) A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:253–262

    Article  PubMed  CAS  Google Scholar 

  • Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schrock H, Nickenig G, Kuschinsky W, Dirnagl U, Laufs U (2003) Mechanisms of stroke protection by physical activity. Ann Neurol 54:582–590

    Article  PubMed  Google Scholar 

  • Erickson KI, Colcombe SJ, Elavsky S, McAuley E, Korol DL, Scalf PE, Kramer AF (2007) Interactive effects of fitness and hormone treatment on brain health in postmenopausal women. Neurobiol Aging 28:179–185

    Article  PubMed  CAS  Google Scholar 

  • Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, McIntosh TK (1995) Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain. Brain Res Mol Brain Res 30:125–130

    Article  PubMed  CAS  Google Scholar 

  • Fujimoto ST, Longhi L, Saatman KE, Conte V, Stocchetti N, McIntosh TK (2004) Motor and cognitive function evaluation following experimental traumatic brain injury. Neurosci Biobehav Rev 28:365–378

    Article  PubMed  Google Scholar 

  • Funk JA, Gohlke J, Kraft AD, McPherson CA, Collins JB, Jean Harry G (2011) Voluntary exercise protects hippocampal neurons from trimethyltin injury: possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity. Brain Behav Immun (in press). doi:10.1016/j.bbi.2011.03.012

  • Gobatto CA, de Mello MA, Sibuya CY, de Azevedo JR, dos Santos LA, Kokubun E (2001) Maximal lactate steady state in rats submitted to swimming exercise. Comp Biochem Physiol A Mol Integr Physiol 130:21–27

    Article  PubMed  CAS  Google Scholar 

  • Hall ED, Yonkers PA, McCall JM, Braughler JM (1988) Effects of the 21-aminosteroid U74006F on experimental head injury in mice. J Neurosurg 68:456–461

    Article  PubMed  CAS  Google Scholar 

  • Hamm TM (1990) Recurrent inhibition to and from motoneurons innervating the flexor digitorum and flexor hallucis longus muscles of the cat. J Neurophysiol 63:395–403

    PubMed  CAS  Google Scholar 

  • Hammacher A, Ward LD, Weinstock J, Treutlein H, Yasukawa K, Simpson RJ (1994) Structure-function analysis of human IL-6: identification of two distinct regions that are important for receptor binding. Protein Sci 3:2280–2293

    Article  PubMed  CAS  Google Scholar 

  • Ivashkova Y, Svetnitsky A, Mayzler O, Pruneau D, Benifla M, Fuxman Y, Cohen A, Artru AA, Shapira Y (2006) Bradykinin B2 receptor antagonism with LF 18-1505T reduces brain edema and improves neurological outcome after closed head trauma in rats. J Trauma 61:879–885

    Article  PubMed  CAS  Google Scholar 

  • Jamme I, Petit E, Divoux D, Gerbi A, Maixent JM, Nouvelot A (1995) Modulation of mouse cerebral Na+, K(+)-ATPase activity by oxygen free radicals. Neuroreport 7:333–337

    PubMed  CAS  Google Scholar 

  • Jang SH (2009) Review of motor recovery in patients with traumatic brain injury. Neurorehabilitation 24:349–353

    PubMed  Google Scholar 

  • Juliet PA, Mao X, Del Bigio MR (2008) Proinflammatory cytokine production by cultured neonatal rat microglia after exposure to blood products. Brain Res 1210:230–239

    Article  PubMed  CAS  Google Scholar 

  • Kossmann T, Hans VH, Imhof HG, Stocker R, Grob P, Trentz O, Morganti-Kossmann C (1995) Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock 4:311–317

    Article  PubMed  CAS  Google Scholar 

  • Laurer HL, Bareyre FM, Lee VM, Trojanowski JQ, Longhi L, Hoover R, Saatman KE, Raghupathi R, Hoshino S, Grady MS, McIntosh TK (2001) Mild head injury increasing the brain’s vulnerability to a second concussive impact. J Neurosurg 95:859–870

    Article  PubMed  CAS  Google Scholar 

  • Lees GJ, Lehmann A, Sandberg M, Hamberger A (1990) The neurotoxicity of ouabain, a sodium-potassium ATPase inhibitor, in the rat hippocampus. Neurosci Lett 120:159–162

    Article  PubMed  CAS  Google Scholar 

  • Lenz A, Franklin GA, Cheadle WG (2007) Systemic inflammation after trauma. Injury 38:1336–1345

    Article  PubMed  Google Scholar 

  • Lenzlinger PM, Saatman KE, Hoover RC, Cheney JA, Bareyre FM, Raghupathi R, Arnold LD, McIntosh TK (2004) Inhibition of vascular endothelial growth factor receptor (VEGFR) signaling by BSF476921 attenuates regional cerebral edema following traumatic brain injury in rats. Restor Neurol Neurosci 22:73–79

    PubMed  CAS  Google Scholar 

  • Li S, Stys PK (2001) Na(+)-K(+)-ATPase inhibition and depolarization induce glutamate release via reverse Na(+)-dependent transport in spinal cord white matter. Neuroscience 107:675–683

    Article  PubMed  CAS  Google Scholar 

  • Lima FD, Souza MA, Furian AF, Rambo LM, Ribeiro LR, Martignoni FV, Hoffmann MS, Fighera MR, Royes LF, Oliveira MS, de Mello CF (2008) Na+,K+-ATPase activity impairment after experimental traumatic brain injury: relationship to spatial learning deficits and oxidative stress. Behav Brain Res 193:306–310

    Article  PubMed  CAS  Google Scholar 

  • Lima FD, Oliveira MS, Furian AF, Souza MA, Rambo LM, Ribeiro LR, Silva LF, Retamoso LT, Hoffmann MS, Magni DV, Pereira L, Fighera MR, Mello CF, Royes LF (2009) Adaptation to oxidative challenge induced by chronic physical exercise prevents Na+,K+-ATPase activity inhibition after traumatic brain injury. Brain Res 1279:147–155

    Article  PubMed  CAS  Google Scholar 

  • Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–S240

    PubMed  CAS  Google Scholar 

  • Marklund N, Morales D, Clausen F, Hanell A, Kiwanuka O, Pitkanen A, Gimbel DA, Philipson O, Lannfelt L, Hillered L, Strittmatter SM, McIntosh TK (2009) Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice. Neuroscience 163:540–551

    Article  PubMed  CAS  Google Scholar 

  • Marquezi ML, Roschel HA, dos Santa Costa A, Sawada LA, Lancha AH Jr (2003) Effect of aspartate and asparagine supplementation on fatigue determinants in intense exercise. Int J Sport Nutr Exerc Metab 13:65–75

    PubMed  CAS  Google Scholar 

  • Mathew P, Graham DI, Bullock R, Maxwell W, McCulloch J, Teasdale G (1994) Focal brain injury: histological evidence of delayed inflammatory response in a new rodent model of focal cortical injury. Acta Neurochir Suppl (Wien) 60:428–430

    CAS  Google Scholar 

  • McIntosh TK, Vink R, Noble L, Yamakami I, Fernyak S, Soares H, Faden AL (1989) Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience 28:233–244

    Article  PubMed  CAS  Google Scholar 

  • Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U (2005) Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 6:775–786

    Article  PubMed  CAS  Google Scholar 

  • Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW (2008) Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflamm 5:13

    Article  Google Scholar 

  • Nimmo AJ, Cernak I, Heath DL, Hu X, Bennett CJ, Vink R (2004) Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats. Neuropeptides 38:40–47

    Article  PubMed  CAS  Google Scholar 

  • Oliveira MS, Furian AF, Rambo LM, Ribeiro LR, Royes LF, Ferreira J, Calixto JB, Otalora LF, Garrido-Sanabria ER, Mello CF (2009) Prostaglandin E2 modulates Na+,K+-ATPase activity in rat hippocampus: implications for neurological diseases. J Neurochem 109:416–426

    Article  PubMed  CAS  Google Scholar 

  • Olsen AL, Morrey JD, Smee DF, Sidwell RW (2007) Correlation between breakdown of the blood-brain barrier and disease outcome of viral encephalitis in mice. Antiviral Res 75:104–112

    Article  PubMed  CAS  Google Scholar 

  • Parachikova A, Nichol KE, Cotman CW (2008) Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis 30:121–129

    Article  PubMed  CAS  Google Scholar 

  • Petersen AM, Pedersen BK (2005) The anti-inflammatory effect of exercise. J Appl Physiol 98:1154–1162

    Article  PubMed  CAS  Google Scholar 

  • Potts MB, Koh SE, Whetstone WD, Walker BA, Yoneyama T, Claus CP, Manvelyan HM, Noble-Haeusslein LJ (2006) Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets. NeuroRx 3:143–153

    Article  PubMed  CAS  Google Scholar 

  • Shlosberg D, Benifla M, Kaufer D, Friedman A (2010) Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6:393–403

    Article  PubMed  CAS  Google Scholar 

  • Skou JC, Esmann M (1992) The Na, K-ATPase. J Bioenerg Biomembr 24:249–261

    PubMed  CAS  Google Scholar 

  • Stahel PF, Kariya K, Shohami E, Barnum SR, Eugster H, Trentz O, Kossmann T, Morganti-Kossmann MC (2000) Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice. J Neuroimmunol 109:164–172

    Article  PubMed  CAS  Google Scholar 

  • Steensberg A (2003) The role of IL-6 in exercise-induced immune changes and metabolism. Exerc Immunol Rev 9:40–47

    PubMed  Google Scholar 

  • Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK (2003) IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab 285:E433–E437

    PubMed  CAS  Google Scholar 

  • Suzuki K, Ota H, Sasagawa S, Sakatani T, Fujikura T (1983) Assay method for myeloperoxidase in human polymorphonuclear leukocytes. Anal Biochem 132:345–352

    Article  PubMed  CAS  Google Scholar 

  • Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW (1994) Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83:113–118

    PubMed  CAS  Google Scholar 

  • Unterberg AW, Stroop R, Thomale UW, Kiening KL, Pauser S, Vollmann W (1997) Characterisation of brain edema following “controlled cortical impact injury” in rats. Acta Neurochir Suppl 70:106–108

    PubMed  CAS  Google Scholar 

  • van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685

    Article  PubMed  Google Scholar 

  • Venturi L, Miranda M, Selmi V, Vitali L, Tani A, Margheri M, De Gaudio AR, Adembri C (2009) Systemic sepsis exacerbates mild post-traumatic brain injury in the rat. J Neurotrauma 26:1547–1556

    Article  PubMed  Google Scholar 

  • Woods JA (2005) Physical activity, exercise, and immune function. Brain Behav Immun 19:369–370

    Article  PubMed  Google Scholar 

  • Wyse AT, Streck EL, Barros SV, Brusque AM, Zugno AI, Wajner M (2000) Methylmalonate administration decreases Na+,K+-ATPase activity in cerebral cortex of rats. Neuroreport 11:2331–2334

    Article  PubMed  CAS  Google Scholar 

  • Ziebell JM, Morganti-Kossmann MC (2010) Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7:22–30

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratório de Bioquímica do Exercício, Departamento de Métodos e Técnicas Desportivas, Centro de Educação Física e Desportos, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Bibiana Castagna Mota, Leticia Pereira, Mauren Assis Souza, Luiz Fernando Almeida Silva, Ana Paula Oliveira Ferreira & Luiz Fernando Freire Royes

  2. Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Mauren Assis Souza, Luiz Fernando Almeida Silva, Danieli Valnes Magni, Ana Paula Oliveira Ferreira, Mauro Schneider Oliveira, Juliano Ferreira, Michele Rechia Fighera & Luiz Fernando Freire Royes

  3. Universidade Federal do Pampa—Campus Itaqui, Itaqui, RS, 97650-000, Brazil

    Mauro Schneider Oliveira & Ana Flávia Furian

  4. Instituto do Cérebro, Serviço de Neurologia, Hospital São Lucas, PUC-RS, Porto Alegre, RS, Brazil

    Michele Rechia Fighera

  5. Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianólpolis, SC, Brazil

    Leidiane Mazzardo-Martins, Morgana Duarte da Silva & Adair Roberto Soares Santos

Authors
  1. Bibiana Castagna Mota
    View author publications

    Search author on:PubMed Google Scholar

  2. Leticia Pereira
    View author publications

    Search author on:PubMed Google Scholar

  3. Mauren Assis Souza
    View author publications

    Search author on:PubMed Google Scholar

  4. Luiz Fernando Almeida Silva
    View author publications

    Search author on:PubMed Google Scholar

  5. Danieli Valnes Magni
    View author publications

    Search author on:PubMed Google Scholar

  6. Ana Paula Oliveira Ferreira
    View author publications

    Search author on:PubMed Google Scholar

  7. Mauro Schneider Oliveira
    View author publications

    Search author on:PubMed Google Scholar

  8. Ana Flávia Furian
    View author publications

    Search author on:PubMed Google Scholar

  9. Leidiane Mazzardo-Martins
    View author publications

    Search author on:PubMed Google Scholar

  10. Morgana Duarte da Silva
    View author publications

    Search author on:PubMed Google Scholar

  11. Adair Roberto Soares Santos
    View author publications

    Search author on:PubMed Google Scholar

  12. Juliano Ferreira
    View author publications

    Search author on:PubMed Google Scholar

  13. Michele Rechia Fighera
    View author publications

    Search author on:PubMed Google Scholar

  14. Luiz Fernando Freire Royes
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Luiz Fernando Freire Royes.

Additional information

Bibiana Castagna Mota and Letícia Pereira contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mota, B.C., Pereira, L., Souza, M.A. et al. Exercise Pre-conditioning Reduces Brain Inflammation and Protects against Toxicity Induced by Traumatic Brain Injury: Behavioral and Neurochemical Approach. Neurotox Res 21, 175–184 (2012). https://doi.org/10.1007/s12640-011-9257-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1007/s12640-011-9257-8

Keywords

Profiles

  1. Ana Flávia Furian View author profile
  2. Morgana Duarte da Silva View author profile