Int J Sports Med 2018; 39(08): 604-612
DOI: 10.1055/a-0608-4635
Physiology & Biochemistry
© Georg Thieme Verlag KG Stuttgart · New York

Effects of Two Training Programs on Transcriptional Levels of Neurotrophins and Glial Cells Population in Hippocampus of Experimental Multiple Sclerosis

Maryam Naghibzadeh
1   Department of Exercise Physiology, Faculty of Sport Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
,
Rouhollah Ranjbar
1   Department of Exercise Physiology, Faculty of Sport Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
,
Mohammad Reza Tabandeh
2   Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
,
Abdolhamid Habibi
1   Department of Exercise Physiology, Faculty of Sport Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
› Author Affiliations
Further Information

Publication History



accepted 30 March 2018

Publication Date:
18 May 2018 (online)

Abstract

The aim of the present study was to investigate the effects of high-intensity interval training (HIIT) versus low-intensity continuous training (LICT) on transcriptional levels of neurotrophic factors and oligodendrocyte/microglia cell loss in a cuprizone (CP) induced animal model of demyelination. Male C57BL/6 mice were assigned to six groups: control (C), cuprizone-induced demyelination (CP), interval training (IT), continuous training (CT), IT plus CP (ITCP), and CT plus CP (CTCP). Training programs on the treadmill were performed for four weeks, and then demyelination was induced by feeding mice a diet containing 0.2% cuprizone for five weeks. Animals that received cuprizone showed poorer motor function, lower expression of BDNF, GDNF, NGF, and fewer oligodendrocytes in the hippocampus compared to the control animals. The numbers of oligodendrocyte and microglia cells increased in the ITCP group compared to the CTCP group (P<0.05). Both training programs increased the mRNA levels of BDNF, GDNF and NGF, and the HIIT program was more effective than the LICT program (P<0.05). Both exercise programs prevented the abnormal neurological movements induced by cuprizone. Our results indicated that HIIT versus LICT had a greater neuroprotective effect against multiple sclerosis by improving gene expression for abnormal neurotrophins and cellular loss in the hippocampus.

 
  • References

  • 1 Afzalpour ME, Chadorneshin HT, Foadoddini M, Eivari HA. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain. Physiol Behav 2015; 147: 78-83
  • 2 Alonso A, Hernán MA. Temporal trends in the incidence of multiple sclerosis A systematic review. Neurology 2008; 71: 129-135
  • 3 Althaus HH, Klöppner S, Schmidt-Schultz T, Schwartz P. Nerve growth factor induces proliferation and enhances fiber regeneration in oligodendrocytes isolated from adult pig brain. Neurosci Lett 1992; 135: 219-223
  • 4 Alvarez-Saavedra M, De Repentigny Y, Yang D, O’Meara RW, Yan K, Hashem LE, Racacho L, Ioshikhes I, Bulman DE, Parks RJ. Voluntary Running Triggers VGF-Mediated Oligodendrogenesis to Prolong the Lifespan of Snf2h-Null Ataxic Mice. Cell Rep 2016; 17: 862-875
  • 5 Arbat-Plana A, Navarro X, Udina E. Effects of forced, passive and voluntary exercise on spinal motoneurons changes after peripheral nerve injury. Eur J Neurosci 2017; 46: 2885-2892
  • 6 Baek S-S. Role of exercise on the brain. J Exerc Rehabil 2016; 12: 380-385
  • 7 Bankston AN, Mandler MD, Feng Y. Oligodendroglia and neurotrophic factors in neurodegeneration. Neurosci Bull 2013; 29: 216-228
  • 8 Bernardes D, Brambilla R, Bracchi-Ricard V, Karmally S, Dellarole A, Carvalho-Tavares J, Bethea JR. Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis. J Neurochem 2016; 136: 63-73
  • 9 Bernardes D, Oliveira-Lima OC, da Silva TV, Faraco CCF, Leite HR, Juliano MA, dos Santos DM, Bethea JR, Brambilla R, Orian JM. Differential brain and spinal cord cytokine and BDNF levels in experimental autoimmune encephalomyelitis are modulated by prior and regular exercise. J Neuroimmunol 2013; 264: 24-34
  • 10 Blesch A, Tuszynski MH. Cellular GDNF delivery promotes growth of motor and dorsal column sensory axons after partial and complete spinal cord transections and induces remyelination. J Comp Neurol 2003; 467: 403-417
  • 11 Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009; 55: 611-622
  • 12 Caggiula M, Batocchi A, Frisullo G, Angelucci F, Patanella A, Sancricca C, Nociti V, Tonali P, Mirabella M. Neurotrophic factors and clinical recovery in relapsing-remitting multiple sclerosis. Scand J Immunol 2005; 62: 176-182
  • 13 Camiletti-Moirón D, Aparicio VA, Nebot E, Medina G, Martínez R, Kapravelou G, Andrade A, Porres JM, López-Jurado M, Aranda P. High-protein diet induces oxidative stress in rat brain: Protective action of high-intensity exercise against lipid peroxidation. Nutr Hosp 2015; 31: 866-874
  • 14 Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R, Yuede CM, Galimberti D, Olivecrona G, Klein RS. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 2015; 129: 429-447
  • 15 Chan JR, Watkins TA, Cosgaya JM, Zhang C, Chen L, Reichardt LF, Shooter EM, Barres BA. NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 2004; 43: 183-191
  • 16 Compston A, Coles A. Multiple sclerosis. The Lancet 2002; 359: 1221-1231
  • 17 Cotman CW, Berchtold NC. Exercise: A behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002; 25: 295-301
  • 18 Dayer D, Tabar MH, Moghimipour E, Tabandeh MR, Ghadiri AA, Bakhshi EA, Orazizadeh M, Ghafari MA. Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells. Cytotherapy 2017; 19: 937-946
  • 19 Di Penta A, Moreno B, Reix S, Fernandez-Diez B, Villanueva M, Errea O, Escala N, Vandenbroeck K, Comella JX, Villoslada P. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PLoS One 2013; 8: e54722
  • 20 Domingues HS, Portugal CC, Socodato R, Relvas JB. Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol 2016; 4: 71
  • 21 Draheim T, Liessem A, Scheld M, Wilms F, Weißflog M, Denecke B, Kensler T, Zendedel A, Beyer C, Kipp M. Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model. Glia 2016; 64: 2219-2230
  • 22 Eckstein C, Saidha S, Levy M. A differential diagnosis of central nervous system demyelination: Beyond multiple sclerosis. J Neurol 2012; 259: 801-816
  • 23 Edge J, Bishop D, Goodman C. The effects of training intensity on muscle buffer capacity in females. Eur J Appl Physiol 2006; 96: 97-105
  • 24 Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex 2003; 13: 845-851
  • 25 Ehninger D, Wang L-P, Klempin F, Römer B, Kettenmann H, Kempermann G. Enriched environment and physical activity reduce microglia and influence the fate of NG2 cells in the amygdala of adult mice. Cell Tissue Res 2011; 345: 69-86
  • 26 Fulmer CG, VonDran MW, Stillman AA, Huang Y, Hempstead BL, Dreyfus CF. Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination. J Neurosci 2014; 34: 8186-8196
  • 27 Gibala MJ, Little JP, MacDonald MJ, Hawley JA. Physiological adaptations to low-volume, high-intensity interval training in health and disease. J Physiol 2012; 590: 1077-1084
  • 28 Goldberg J, Daniel M, van Heuvel Y, Victor M, Beyer C, Clarner T, Kipp M. Short-term cuprizone feeding induces selective amino acid deprivation with concomitant activation of an integrated stress response in oligodendrocytes. Cell Mol Neurobiol 2013; 33: 1087-1098
  • 29 Gonsalvez DG, Tran G, Fletcher JL, Hughes RA, Hodgkinson S, Wood RJ, Yoo SW, De Silva M, Agnes WW, McLean C. A brain-derived neurotrophic factor-based p75NTR peptide mimetic ameliorates experimental autoimmune neuritis induced axonal pathology and demyelination. eNeuro 2017; 4: 1-17
  • 30 Harriss DJ, Macsween A, Atkinson G. Standards for ethics in sport and exercise science research: 2018 update. Int J Sports Med 2017; 38: 1126-1131
  • 31 Hibbits N, Pannu R, Wu TJ, Armstrong RC. Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination. ASN Neuro 2009; 1(3). pii: e00013
  • 32 Hibbits N, Yoshino J, Le TQ, Armstrong RC. Astrogliosis during acute and chronic cuprizone demyelination and implications for remyelination. ASN Neuro 2012; 4: 393-408
  • 33 Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H. The neuroprotective effect of inflammation: Implications for the therapy of multiple sclerosis. Neurol Sci 2006; 27: S1-S7
  • 34 Houdebine L, Gallelli CA, Rastelli M, Sampathkumar NK, Grenier J. Effect of physical exercise on brain and lipid metabolism in mouse models of multiple sclerosis. Chem Phys Lipids 2017; 207(Pt B): 127-134
  • 35 Huang EJ, Reichardt LF. Neurotrophins: Roles in neuronal development and function. Annu Rev Neurosci 2001; 24: 677-736
  • 36 Kalinowska-Lyszczarz A, Losy J. The role of neurotrophins in multiple sclerosis—pathological and clinical implications. Int J Mol Sci 2012; 13: 13713-13725
  • 37 Kehrberg AMH. Neuronal nitric oxide protects the developing cerebellum against alcohol-induced functional and cellular deficits. University of Iowa; USA. ProQuest 2006
  • 38 Kim T-W, Sung Y-H. Regular exercise promotes memory function and enhances hippocampal neuroplasticity in experimental autoimmune encephalomyelitis mice. Neurosci 2017; 346: 173-181
  • 39 Kipp M, Clarner T, Dang J, Copray S, Beyer C. The cuprizone animal model: new insights into an old story. Acta Neuropathol 2009; 118: 723-736
  • 40 Kipp M, Nyamoya S, Hochstrasser T, Amor S. Multiple sclerosis animal models: A clinical and histopathological perspective. Brain Pathol 2017; 27: 123-137
  • 41 Klaren RE, Stasula U, Steelman AJ, Hernandez J, Pence BD, Woods JA, Motl RW. Effects of exercise in a relapsing-remitting model of experimental autoimmune encephalomyelitis. J Neurosci Res 2016; 94: 907-914
  • 42 Kohman RA, DeYoung EK, Bhattacharya TK, Peterson LN, Rhodes JS. Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice. Brain Behav Immun 2012; 26: 803-810
  • 43 Koutsoudaki PN, Skripuletz T, Gudi V, Moharregh-Khiabani D, Hildebrandt H, Trebst C, Stangel M. Demyelination of the hippocampus is prominent in the cuprizone model. Neurosci Lett 2009; 451: 83-88
  • 44 Krityakiarana W, Espinosa-Jeffrey A, Ghiani C, Zhao P, Topaldjikian N, Gomez-Pinilla F, Yamaguchi M, Kotchabhakdi N, De Vellis J. Voluntary exercise increases oligodendrogenesis in spinal cord. Int J Neurosci 2010; 120: 280-290
  • 45 Labunets I, Melnyk N, Rodnichenko A, Rymar S, Utko N. Cuprizone-induced disorders of central nervous system neurons, behavioral reactions, brain activity of macrophages and antioxidant enzymes in the mice of different ages: Role of leukemia inhibitory factor in their improvement. J Aging Geriatr Med 2017; 1: 1-8
  • 46 Lampron A, Larochelle A, Laflamme N, Préfontaine P, Plante M-M, Sánchez MG, Yong VW, Stys PK, Tremblay M-È, Rivest S. Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J Exp Med 2015; 212: 481-495
  • 47 Learmonth YC, Motl RW. Physical activity and exercise training in multiple sclerosis: A review and content analysis of qualitative research identifying perceived determinants and consequences. Disabil Rehabil 2016; 38: 1227-1242
  • 48 Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443: 787-795
  • 49 Lucas SJ, Cotter JD, Brassard P, Bailey DM. High-intensity interval exercise and cerebrovascular health: Curiosity, cause, and consequence. J Cereb Blood Flow Metab 2015; 35: 902-911
  • 50 Makar TK, Bever CT, Singh IS, Royal W, Sahu SN, Sura TP, Sultana S, Sura KT, Patel N, Dhib-Jalbut S. Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J Neuroimmunol 2009; 210: 40-51
  • 51 Marquez CMS, Vanaudenaerde B, Troosters T, Wenderoth N. High-intensity interval training evokes larger serum BDNF levels compared with intense continuous exercise. J Appl Physiol 2015; 119: 1363-1373
  • 52 Matsushima GK, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 2001; 11: 107-116
  • 53 McTigue DM, Horner PJ, Stokes BT, Gage FH. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 1998; 18: 5354-5365
  • 54 Meyer P, Gayda M, Juneau M, Nigam A. High-intensity aerobic interval exercise in chronic heart failure. Curr Heart Fail Rep 2013; 10: 130-138
  • 55 Mifflin KA, Frieser E, Benson C, Baker G, Kerr BJ. Voluntary wheel running differentially affects disease outcomes in male and female mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 2017; 305: 135-144
  • 56 Miron VE, Boyd A, Zhao J-W, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 2013; 16: 1211-1218
  • 57 Miron VE, Franklin RJ. Macrophages and CNS remyelination. J Neurochem 2014; 130: 165-171
  • 58 Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol 2012; 8: 487-497
  • 59 Patel DI, White LJ. Effect of 10-day forced treadmill training on neurotrophic factors in experimental autoimmune encephalomyelitis. Appl Physiol Nutr Metab 2013; 38: 194-199
  • 60 Perrey S. Promoting motor function by exercising the brain. Brain Sci 2013; 3: 101-122
  • 61 Pilutti LA, Platta ME, Motl RW, Latimer-Cheung AE. The safety of exercise training in multiple sclerosis: A systematic review. J Neurol Sci 2014; 343: 3-7
  • 62 Pin-Barre C, Constans A, Brisswalter J, Pellegrino C, Laurin J. Effects of high-versus moderate-intensity training on neuroplasticity and functional recovery after focal ischemia. Stroke 2017; 48: 2855-2864
  • 63 Praet J, Guglielmetti C, Berneman Z, Van der Linden A, Ponsaerts P. Cellular and molecular neuropathology of the cuprizone mouse model: Clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 2014; 47: 485-505
  • 64 Pryor WM, Freeman KG, Larson RD, Edwards GL, White LJ. Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis. J Neurosci Res 2015; 93: 697-706
  • 65 Qiao D, Hou L, Liu X. Influence of intermittent anaerobic exercise on mouse physical endurance and antioxidant components. Br J Sports Med 2006; 40: 214-218
  • 66 Radak Z, Ihasz F, Koltai E, Goto S, Taylor A, Boldogh I. The redox-associated adaptive response of brain to physical exercise. Free Radic Res 2014; 48: 84-92
  • 67 Rumrill Jr PD. Multiple sclerosis: Medical and psychosocial aspects, etiology, incidence, and prevalence. J Vocat Rehabil 2009; 31: 75-82
  • 68 Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E, Berger K, Kipp M, Baumgärtner W, Stangel M. Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain 2013; 136: 147-167
  • 69 Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001; 24: 1217-1281
  • 70 Souza PS, Gonçalves ED, Pedroso GS, Farias HR, Junqueira SC, Marcon R, Tuon T, Cola M, Silveira PC, Santos AR. Physical exercise attenuates experimental autoimmune encephalomyelitis by inhibiting peripheral immune response and blood-brain barrier disruption. Mol Neurobiol 2017; 1-15
  • 71 Stangel M, Kuhlmann T, Matthews PM, Kilpatrick TJ. Achievements and obstacles of remyelinating therapies in multiple sclerosis. Nat Rev Neurol 2017; 13: 742-754
  • 72 Torkildsen Ø, Brunborg L, Myhr KM, Bø L. The cuprizone model for demyelination. Acta Neurol Scand 2008; 117: 72-76
  • 73 Wens I, Dalgas U, Vandenabeele F, Grevendonk L, Verboven K, Hansen D, Eijnde BO. High intensity exercise in multiple sclerosis: Effects on muscle contractile characteristics and exercise capacity, a randomised controlled trial. PLoS One 2015; 10: e0133697
  • 74 White LJ, Castellano V. Exercise and brain health—implications for multiple sclerosis. Sports Med 2008; 38: 91-100
  • 75 Yoon H, Kleven A, Paulsen A, Kleppe L, Wu J, Ying Z, Gomez-Pinilla F, Scarisbrick IA. Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system. Biochim Biophys Acta 2016; 1862: 545-555
  • 76 Zimmer P, Bloch W, Schenk A, Oberste M, Riedel S, Kool J, Langdon D, Dalgas U, Kesselring J, Bansi J. High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: A randomized controlled trial. Mult Scler 2017; 1: 1352458517728342
  • 77 Zimmermann J, Emrich M, Krauthausen M, Saxe S, Nitsch L, Heneka MT, Campbell IL, Müller M. IL-17 A promotes granulocyte infiltration, myelin loss, microglia activation, and behavioral deficits during cuprizone-induced demyelination. Mol Neurobiol 2017; 1-12