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The effects of early exercise in traumatic brain-injured rats with changes in motor ability, brain tissue, and biomarkers

  • Kim, Chung Kwon (Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University) ;
  • Park, Jee Soo (Single Cell Network Research Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Eunji (Medical Innovation Technology Inc. (MEDINNO Inc.)) ;
  • Oh, Min-Kyun (Department of Rehabilitation Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University Graduate School of Medicine) ;
  • Lee, Yong-Taek (Department of Physical & Rehabilitation Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Yoon, Kyung Jae (Department of Physical & Rehabilitation Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Joo, Kyeung Min (Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University) ;
  • Lee, Kyunghoon (Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University) ;
  • Park, Young Sook (Department of Physical & Rehabilitation Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine)
  • Received : 2022.06.13
  • Accepted : 2022.08.17
  • Published : 2022.10.31

Abstract

Traumatic brain injury (TBI) is brain damage which is caused by the impact of external mechanical forces. TBI can lead to the temporary or permanent impairment of physical and cognitive abilities, resulting in abnormal behavior. We recently observed that a single session of early exercise in animals with TBI improved their behavioral performance in the absence of other cognitive abnormalities. In the present study, we investigated the therapeutic effects of continuous exercise during the early stages of TBI in rats. We found that continuous low-intensity exercise in early-stage improves the locomotion recovery in the TBI of animal models; however, it does not significantly enhance short-term memory capabilities. Moreover, continuous early exercise not only reduces the protein expression of cerebral damage-related markers, such as Glial Fibrillary Acid Protein (GFAP), Neuron-Specific Enolase (NSE), S100β, Protein Gene Products 9.5 (PGP9.5), and Heat Shock Protein 70 (HSP70), but it also decreases the expression of apoptosis-related protein BAX and cleaved caspase 3. Furthermore, exercise training in animals with TBI decreases the microglia activation and the expression of inflammatory cytokines in the serum, such as CCL20, IL-13, IL-1α, and IL-1β. These findings thus demonstrate that early exercise therapy for TBI may be an effective strategy in improving physiological function, and that serum protein levels are useful biomarkers for the predicition of the effectiveness of early exercise therapy.

Keywords

Acknowledgement

This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean Government (MSIP) (NRF-2016R1A5A2945889, 2017R1A2B4010100, 2018 R1D1 A1B07050274, and NRF-2020R1F1A1073261).

References

  1. Quaglio G, Gallucci M, Brand H, Dawood A and Cobello F (2017) Traumatic brain injury: a priority for public health policy. Lancet Neurol 16, 951-952 https://doi.org/10.1016/S1474-4422(17)30370-8
  2. Borg J, Roe C, Nordenbo A, Andelic N, de Boussard C and af Geijerstam JL (2011) Trends and challenges in the early rehabilitation of patients with traumatic brain injury: a Scandinavian perspective. Am J Phys Med Rehabil 90, 65-73 https://doi.org/10.1097/PHM.0b013e3181fc80e7
  3. van Praag H, Kempermann G and Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2, 266-270 https://doi.org/10.1038/6368
  4. Isaacs KR, Anderson BJ, Alcantara AA, Black JE and Greenough WT (1992) Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning. J Cereb Blood Flow Metab 12, 110-119 https://doi.org/10.1038/jcbfm.1992.14
  5. Swain RA, Harris AB, Wiener EC et al (2003) Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 117, 1037-1046 https://doi.org/10.1016/S0306-4522(02)00664-4
  6. Zhu XL, Poon WS, Chan CC and Chan SS (2007) Does intensive rehabilitation improve the functional outcome of patients with traumatic brain injury (TBI)? a randomized controlled trial. Brain Inj 21, 681-690 https://doi.org/10.1080/02699050701468941
  7. Kurowski BG, Hugentobler J, Quatman-Yates C et al (2017) Aerobic exercise for adolescents with prolonged symptoms after mild traumatic brain injury: an exploratory randomized clinical trial. J Head Trauma Rehabil 32, 79-89 https://doi.org/10.1097/HTR.0000000000000238
  8. Humm JL, Kozlowski DA, James DC, Gotts JE and Schallert T (1998) Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period. Brain Res 783, 286-292 https://doi.org/10.1016/S0006-8993(97)01356-5
  9. Griesbach GS, Gomez-Pinilla F and Hovda DA (2007) Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent. J Neurotrauma 24, 1161-1171 https://doi.org/10.1089/neu.2006.0255
  10. Lippert-Gruner M, Maegele M, Pokorny J et al (2007) Early rehabilitation model shows positive effects on neural degeneration and recovery from neuromotor deficits following traumatic brain injury. Physiol Res 56, 359-368 https://doi.org/10.33549/physiolres.930971
  11. Bernhardt J, Churilov L, Ellery F et al (2016) Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT). Neurology 86, 2138-2145 https://doi.org/10.1212/WNL.0000000000002459
  12. Kawata K, Liu CY, Merkel SF, Ramirez SH, Tierney RT and Langford D (2016) Blood biomarkers for brain injury: what are we measuring? Neurosci Biobehav Rev 68, 460-473 https://doi.org/10.1016/j.neubiorev.2016.05.009
  13. Olivecrona M, Rodling-Wahlstrom M, Naredi S and Koskinen LO (2009) S-100B and neuron specific enolase are poor outcome predictors in severe traumatic brain injury treated by an intracranial pressure targeted therapy. J Neurol Neurosurg Psychiatry 80, 1241-1247 https://doi.org/10.1136/jnnp.2008.158196
  14. Huang XJ, Glushakova O, Mondello S, Van K, Hayes RL and Lyeth BG (2015) Acute temporal profiles of serum levels of UCH-L1 and GFAP and relationships to neuronal and astroglial pathology following traumatic brain injury in rats. J Neurotrauma 32, 1179-1189 https://doi.org/10.1089/neu.2015.3873
  15. Thelin EP, Jeppsson E, Frostell A et al (2016) Utility of neuron-specific enolase in traumatic brain injury; relations to S100B levels, outcome, and extracranial injury severity. Crit Care 20, 285 https://doi.org/10.1186/s13054-016-1450-y
  16. da Rocha AB, Zanoni C, de Freitas GR et al (2005) Serum Hsp70 as an early predictor of fatal outcome after severe traumatic brain injury in males. J Neurotrauma 22, 966-977 https://doi.org/10.1089/neu.2005.22.966
  17. Yoon KJ and Kim DY (2018) Immediate effects of a single exercise on behavior and memory in the early period of traumatic brain injury in rats. Ann Rehabil Med 42, 643-651 https://doi.org/10.5535/arm.2018.42.5.643
  18. Zurek J and Fedora M (2012) The usefulness of S100B, NSE, GFAP, NF-H, secretagogin and Hsp70 as a predictive biomarker of outcome in children with traumatic brain injury. Acta Neurochir (Wien) 154, 93-103; discussion 103 https://doi.org/10.1007/s00701-011-1175-2
  19. Amoo M, Henry J, O'Halloran PJ et al (2022) S100B, GFAP, UCH-L1 and NSE as predictors of abnormalities on CT imaging following mild traumatic brain injury: a systematic review and meta-analysis of diagnostic test accuracy. Neurosurg Rev 45, 1171-1193 https://doi.org/10.1007/s10143-021-01678-z
  20. Das M, Mayilsamy K, Tang X et al (2019) Pioglitazone treatment prior to transplantation improves the efficacy of human mesenchymal stem cells after traumatic brain injury in rats. Sci Rep 9, 13646 https://doi.org/10.1038/s41598-019-49428-y
  21. Chiu CC, Liao YE, Yang LY et al (2016) Neuroinflammation in animal models of traumatic brain injury. J Neurosci Methods 272, 38-49 https://doi.org/10.1016/j.jneumeth.2016.06.018
  22. Cooper C, Moon HY and van Praag H (2018) On the run for hippocampal plasticity. Cold Spring Harb Perspect Med 8, a029736 https://doi.org/10.1101/cshperspect.a029736
  23. Mychasiuk R, Hehar H, Ma I, Candy S and Esser MJ (2016) Reducing the time interval between concussion and voluntary exercise restores motor impairment, short-term memory, and alterations to gene expression. Eur J Neurosci 44, 2407-2417 https://doi.org/10.1111/ejn.13360
  24. Weinstein AA, Chin LMK, Collins J, Goel D, Keyser RE and Chan L (2017) Effect of aerobic exercise training on mood in people with traumatic brain injury: a pilot study. J Head Trauma Rehabil 32, 49-56
  25. Ghajar J (2000) Traumatic brain injury. Lancet 356, 923-929 https://doi.org/10.1016/S0140-6736(00)02689-1
  26. Henry LC, Tremblay S, Leclerc S et al (2011) Metabolic changes in concussed American football players during the acute and chronic post-injury phases. BMC Neurol 11, 105 https://doi.org/10.1186/1471-2377-11-105
  27. Wyllie AH, Kerr JF and Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68, 251-306 https://doi.org/10.1016/S0074-7696(08)62312-8
  28. Kanduc D, Mittelman A, Serpico R et al (2002) Cell death: apoptosis versus necrosis (review). Int J Oncol 21, 165-170
  29. Gillies LA and Kuwana T (2014) Apoptosis regulation at the mitochondrial outer membrane. J Cell Biochem 115, 632-640 https://doi.org/10.1002/jcb.24709
  30. Tao L, Chen X, Qin Z and Bian S (2006) Could NF-kappaB and caspase-3 be markers for estimation of post-interval of human traumatic brain injury? Forensic Sci Int 162, 174-177 https://doi.org/10.1016/j.forsciint.2006.06.021
  31. Nathoo N, Narotam PK, Agrawal DK et al (2004) Influence of apoptosis on neurological outcome following traumatic cerebral contusion. J Neurosurg 101, 233-240 https://doi.org/10.3171/jns.2004.101.2.0233
  32. Clark RS, Kochanek PM, Chen M et al (1999) Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J 13, 813-821 https://doi.org/10.1096/fasebj.13.8.813
  33. Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J and Borlongan CV (2013) Microglia activation as a biomarker for traumatic brain injury. Front Neurol 4, 30
  34. Kumar A and Loane DJ (2012) Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun 26, 1191-1201 https://doi.org/10.1016/j.bbi.2012.06.008
  35. Ozen I, Ruscher K, Nilsson R, Flygt J, Clausen F and Marklund N (2020) Interleukin-1 beta neutralization attenuates traumatic brain injury-induced microglia activation and neuronal changes in the globus pallidus. Int J Mol Sci 21, 387 https://doi.org/10.3390/ijms21020387