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Activation of BDNF- and VEGF-mediated Neuroprotection by Treadmill Exercise Training in Experimental Stroke

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Abstract

Early treatment of ischemic stroke is one of the most effective ways to reduce brains’ cell death and promote functional recovery. This study was designed to examine the effect of aerobic exercise on post ischemia/reperfusion injury on concentration and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after inducing a neuronal loss in CA1 region of hippocampus in Male Wistar rats. Three experimental groups including sham(S), ischemia/reperfusion-control (IRC) and ischemia/reperfusion exercise (IRE) were used for this purpose. The rats in the IRE group received a bilateral carotid artery occlusion treatment. They ran for 45 minutes on a treadmill five days per week for eight consecutive weeks. Cresyl violet (Nissl), Hematoxylin (H & E) and Eosin staining procedure were used to determine the extent of damage. A ladder rung walking task was used to assess the functional impairments and recovery after the ischemic lesion. ELISA and immunohistochemistry method were employed to measure BDNF and VEGF protein expressions. The result showed that the brain ischemia/reperfusion condition increased the cell death in hippocampal CA1 neurons and impaired motor performance on the ladder rung task whereas the aerobic exercise program significantly decreased the brain cell’s death and improved motor skill performance. It was concluded that ischemic brain lesion decreased the BDNF and VEGF expression. It seems that the aerobic exercise following the ischemia/reperfusion potentially promotes neuroprotective mechanisms and neuronal repair and survival mediated partly by BDNF and other pathways.

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References

  • Aboutaleb N, Shamsaei N, Rajabi H, Khaksari M, Erfani S, Nikbakht F, Motamedi P, Shahbazi A (2016) Protection of hippocampal CA1 neurons against ischemia/reperfusion injury by exercise preconditioning via modulation of Bax/Bcl-2 ratio and prevention of caspase-3 activation. Basic Clin Neurosci 7(1):21

    CAS  PubMed  PubMed Central  Google Scholar 

  • Antonow-Schlorke I, Ehrhardt J, Knieling M (2013) Modification of the ladder rung walking task—New options for analysis of skilled movements. Stroke Res Treat 2013:418627

  • Belov Kirdajova D, Kriska J, Tureckova J, Anderova M (2020) Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells. Front Cell Neurosci 14:51

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bendel O, Bueters T, von Euler M, Ögren SO, Sandin J, von Euler G (2005) Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory. J Cereb Blood Flow Metab 25(12):1586–1595

    Article  CAS  PubMed  Google Scholar 

  • Bernhardt J, Dewey H, Thrift A, Collier J, Donnan G (2008) A very early rehabilitation trial for stroke (AVERT) phase II safety and feasibility. Stroke 39(2):390–396

    Article  PubMed  Google Scholar 

  • Bernhardt J, Langhorne P, Lindley RI, Thrift AG, Ellery F, Collier J, Churilov L, Moodie M, Dewey H, Donnan G (2015) Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. Lancet 386(9988):46–55

    Article  Google Scholar 

  • Berretta A, Tzeng Y-C, Clarkson AN (2014) Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor. Expert Rev Neurother 14(11):1335–1344

    Article  CAS  PubMed  Google Scholar 

  • Bonde C, Noraberg J, Noer H, Zimmer J (2005) Ionotropic glutamate receptors and glutamate transporters are involved in necrotic neuronal cell death induced by oxygen–glucose deprivation of hippocampal slice cultures. Neuroscience 136(3):779–794

    Article  CAS  PubMed  Google Scholar 

  • Burnett MG, Shimazu T, Szabados T, Muramatsu H, Detre JA, Greenberg JH (2006) Electrical forepaw stimulation during reversible forebrain ischemia decreases infarct volume. Stroke 37(5):1327–1331

    Article  PubMed  Google Scholar 

  • Cárdenas-Rivera A, Campero-Romero AN, Heras-Romero Y, Penagos-Puig A, Rincón-Heredia R, Tovar-y-Romo LB (2019) Early post-stroke activation of Vascular Endothelial Growth Factor Receptor 2 hinders the Receptor 1-dependent neuroprotection afforded by the endogenous ligand. Front Cell Neurosci 13:270

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chang MC, Park CR, Rhie SH, Shim WH, Kim DY (2019) Early treadmill exercise increases macrophage migration inhibitory factor expression after cerebral ischemia/reperfusion. Neural Regen Res 14(7):1230

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen J, Venkat P, Zacharek A, Chopp M (2014) Neurorestorative therapy for stroke. Front Hum Neurosci 8:382

    PubMed  PubMed Central  Google Scholar 

  • Chen Z, Hu Q, Xie Q, Wu S, Pang Q, Liu M, Zhao Y, Tu F, Liu C, Chen X (2019) Effects of treadmill exercise on motor and cognitive function recovery of MCAO mice through the caveolin-1/VEGF signaling pathway in ischemic penumbra. Neurochem Res 44(4):930–946

    Article  CAS  PubMed  Google Scholar 

  • DeBow SB, Davies ML, Clarke HL, Colbourne F (2003) Constraint-induced movement therapy and rehabilitation exercises lessen motor deficits and volume of brain injury after striatal hemorrhagic stroke in rats. Stroke 34(4):1021–1026

    Article  PubMed  Google Scholar 

  • Deng G, Qiu Z, Li D, Fang Y, Zhang S (2017) Delayed administration of guanosine improves long-term functional recovery and enhances neurogenesis and angiogenesis in a mouse model of photothrombotic stroke. Mol Med Rep 15(6):3999–4004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding Y-H, Luan X-D, Li J, Rafols JA, Guthinkonda M, Diaz FG, Ding Y (2004) Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke. Curr Neurovasc Res 1(5):411–420

    Article  CAS  PubMed  Google Scholar 

  • Diserens K, Michel P, Bogousslavsky J (2006) Early mobilisation after stroke: review of the literature. Cerebrovasc Dis 22(2-3):183–190

    Article  PubMed  Google Scholar 

  • Dudar J, Whishaw I, Szerb J (1979) Release of acetylcholine from the hippocampus of freely moving rats during sensory stimulation and running. Neuropharmacology 18(8-9):673–678

    Article  CAS  PubMed  Google Scholar 

  • Eltzschig HK, Eckle T (2011) Ischemia and reperfusion—from mechanism to translation. Nat Med 17(11):1391–1401

    Article  CAS  PubMed  Google Scholar 

  • Erfani S, Khaksari M, Oryan S, Shamsaei N, Aboutaleb N, Nikbakht F (2015) Nampt/PBEF/visfatin exerts neuroprotective effects against ischemia/reperfusion injury via modulation of Bax/Bcl-2 ratio and prevention of caspase-3 activation. J Mol Neurosci 56(1):237–243

    Article  CAS  PubMed  Google Scholar 

  • Erfani S, Moghimi A, Aboutaleb N, Khaksari M (2018) Nesfatin-1 improve spatial memory impairment following transient global cerebral ischemia/reperfusion via inhibiting microglial and caspase-3 activation. J Mol Neurosci 65(3):377–384

    Article  CAS  PubMed  Google Scholar 

  • Feldman AT, Wolfe D (2014) Tissue processing and hematoxylin and eosin staining. Methods Mol Biol 1180:31–43

  • Hayashi T, Noshita N, Sugawara T, Chan PH (2003) Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 23(2):166–180

    Article  CAS  PubMed  Google Scholar 

  • Himi N, Takahashi H, Okabe N, Nakamura E, Shiromoto T, Narita K, Koga T, Miyamoto O (2016) Exercise in the early stage after stroke enhances hippocampal brain-derived neurotrophic factor expression and memory function recovery. J Stroke Cerebrovasc Dis 25(12):2987–2994

    Article  PubMed  Google Scholar 

  • Hofman F (2002) Immunohistochemistry. Curr Protoc Immunol 49(1):21.24 21-21.24. 23

    Google Scholar 

  • Humm JL, Kozlowski DA, James DC, Gotts JE, Schallert T (1998) Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period. Brain Res 783(2):286–292

    Article  CAS  PubMed  Google Scholar 

  • Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2012) Cell biology of ischemia/reperfusion injury. Journal 298(Issue):229–317

    CAS  Google Scholar 

  • Katsura K-I, Kristián T, Smith M-L, Siesjö BK (1994) Acidosis induced by hypercapnia exaggerates ischemic brain damage. J Cereb Blood Flow Metab 14(2):243–250

    Article  CAS  PubMed  Google Scholar 

  • Kiernan JA (1999) Histological and histochemical methods: theory and practice. Shock 12(6):479

    Google Scholar 

  • Kirino T, Sano K (1984) Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol 62(3):201–208

    Article  CAS  PubMed  Google Scholar 

  • Knecht S, Hesse S, Oster P (2011) Rehabilitation after stroke. Dtsch Arztebl Int 108(36):600

    PubMed  PubMed Central  Google Scholar 

  • Kokaia Z, Andsberg G, Yan Q, Lindvall O (1998) Rapid alterations of BDNF protein levels in the rat brain after focal ischemia: evidence for increased synthesis and anterograde axonal transport. Exp Neurol 154(2):289–301

    Article  CAS  PubMed  Google Scholar 

  • Kozlowski DA, James DC, Schallert T (1996) Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 16(15):4776–4786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai TW, Zhang S, Wang YT (2014) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157–188

    Article  CAS  PubMed  Google Scholar 

  • Li F, Geng X, Khan H, Pendy JT Jr, Peng C, Li X, Rafols JA, Ding Y (2017a) Exacerbation of brain injury by post-stroke exercise is contingent upon exercise initiation timing. Front Cell Neurosci 11:311

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li F, Pendy JT Jr, Ding JN, Peng C, Li X, Shen J, Wang S, Geng X (2017b) Exercise rehabilitation immediately following ischemic stroke exacerbates inflammatory injury. Neurol Res 39(6):530–537

    Article  PubMed  Google Scholar 

  • Li ZC, Jia YP, Wang Y, Qi JL, Han XP (2018) Effects of dexmedetomidine post-treatment on BDNF and VEGF expression following cerebral ischemia/reperfusion injury in rats. Mol Med Rep 17(4):6033–6037

    CAS  PubMed  Google Scholar 

  • Liu W, Wang X,O’Connor M, Wang G, Han F (2020) Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities. Neural Plast 2020:1969482

  • Marin R, Williams A, Hale S, Burge B, Mense M, Bauman R, Tortella F (2003) The effect of voluntary exercise exposure on histological and neurobehavioral outcomes after ischemic brain injury in the rat. Physiol Behav 80(2-3):167–175

    Article  CAS  PubMed  Google Scholar 

  • Matsuda F, Sakakima H, Yoshida Y (2010) The effects of early exercise on brain damage and recovery after focal cerebral infarction in rats. Acta Physiol (Oxf) 201(2):275–87

  • Metz GA, Whishaw IQ (2002) Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore-and hindlimb stepping, placing, and co-ordination. J Neurosci Methods 115(2):169–179

    Article  PubMed  Google Scholar 

  • Metz GA, Whishaw IQ (2009) The ladder rung walking task: a scoring system and its practical application. JoVE (Journal of Visualized Experiments) 28:e1204

    Google Scholar 

  • Metz GA, Antonow-Schlorke I, Witte OW (2005) Motor improvements after focal cortical ischemia in adult rats are mediated by compensatory mechanisms. Behav Brain Res 162(1):71–82

    Article  PubMed  Google Scholar 

  • Moniri SF, Hedayatpour A, Hassanzadeh G, Vazirian M, Karimian M, Belaran M, Mehr SE, Akbari M (2017) The Effect of Rosa Damascena Extract on Expression of Neurotrophic Factors in the CA1 Neurons of Adult Rat Hippocampus Following Ischemia. Acta Med Iran 55(12):779–784

  • Moon S-K, Alaverdashvili M, Cross AR, Whishaw IQ (2009) Both compensation and recovery of skilled reaching following small photothrombotic stroke to motor cortex in the rat. Exp Neurol 218(1):145–153

    Article  PubMed  Google Scholar 

  • Nadia Sharifi Z, Abolhassani F, Hassanzadeh G, Zarrindast MR, Movassaghi S (2014) Neuroprotective treatment with FK506 reduces hippocampal damage and prevents learning and memory deficits after transient global ischemia in rat. Arch Neurosci 1(1):35–40

    Article  Google Scholar 

  • Paxinos G, Franklin KB (2019) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates. 5th Edition

  • Rama R, García JC (2016) Excitotoxicity and oxidative stress in acute stroke. Ischemic Stroke Updates, chapter 2, pp 17–33

  • Schmidt-Kastner R, Wietasch K, Weigel H, Eysel U (1993) Immunohistochemical staining for glial fibrillary acidic protein (GFAP) after deafferentation or ischemic infarction in rat visual system: features of reactive and damaged astrocytes. Int J Dev Neurosci 11(2):157–174

    Article  CAS  PubMed  Google Scholar 

  • Schmidt-Kastner R, Truettner J, Lin B, Zhao W, Saul I, Busto R, Ginsberg MD (2001) Transient changes of brain-derived neurotrophic factor (BDNF) mRNA expression in hippocampus during moderate ischemia induced by chronic bilateral common carotid artery occlusions in the rat. Mol Brain Res 92(1-2):157–166

    Article  CAS  PubMed  Google Scholar 

  • Seydyousefi M, Moghanlou AE, Metz GA, Gursoy R, Faghfoori MH, Mirghani SJ, Faghfoori Z (2019) Exogenous adenosine facilitates neuroprotection and functional recovery following cerebral ischemia in rats. Brain Res Bull 153:250–256

    Article  CAS  PubMed  Google Scholar 

  • Stroke Unit Trialists’ Collaboration (2013) Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst Rev 2013(9):CD000197

  • Teixeira AL, Barbosa IG, Diniz BS, Kummer A (2010) Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med 4(6):871–887

    Article  CAS  PubMed  Google Scholar 

  • Tian S, Zhang Y, Tian S, Yang X, Yu K, Zhang Y, Shen X, Zhang L, Sun Y, Xie H (2013) Early exercise training improves ischemic outcome in rats by cerebral hemodynamics. Brain Res 1533:114–121

    Article  CAS  PubMed  Google Scholar 

  • Uchino H, Lindvall O, Siesjö B, Kokaia Z (1997) Hyperglycemia and hypercapnia suppress BDNF gene expression in vulnerable regions after transient forebrain ischemia in the rat. J Cereb Blood Flow Metab 17(12):1303–1308

    Article  CAS  PubMed  Google Scholar 

  • Wahl P, Jansen F, Achtzehn S, Schmitz T, Bloch W, Mester J, Werner N (2014) Effects of high intensity training and high volume training on endothelial microparticles and angiogenic growth factors. PLoS One 9(4):e96024

    Article  PubMed  PubMed Central  Google Scholar 

  • Wallace DG, Winter SS, Metz GA (2012) Serial pattern learning during skilled walking. J Integr Neurosci 11(01):17–32

    Article  PubMed  Google Scholar 

  • Williams-Karnesky RL, Stenzel-Poore MP (2009) Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant. Curr Neuropharmacol 7(3):217–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing Y, Yang S-D, Dong F, Wang M-M, Feng Y-S, Zhang F (2018) The beneficial role of early exercise training following stroke and possible mechanisms. Life Sci 198:32–37

    Article  CAS  PubMed  Google Scholar 

  • Yang Y-R, Wang R-Y, Wang PS-G (2003) Early and late treadmill training after focal brain ischemia in rats. Neurosci Lett 339(2):91–94

    Article  CAS  PubMed  Google Scholar 

  • Zhang P, Zhang Q, Pu H, Wu Y, Bai Y, Vosler PS, Chen J, Shi H, Gao Y, Hu Y (2012) Very early-initiated physical rehabilitation protects against ischemic brain injury. Front Biosci (Elite Ed) 4:2476–2489

    Google Scholar 

  • Zhang P, Yu H, Zhou N, Zhang J, Wu Y, Zhang Y, Bai Y, Jia J, Zhang Q, Tian S (2013) Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model. J Neuroeng Rehab 10(1):43

    Article  Google Scholar 

  • Zhang P, Xianglei J, Hongbo Y, Zhang J, Xu C (2015) Neuroprotection of early locomotor exercise poststroke: evidence from animal studies. Can J Neurol Sci 42(4):213–220

    Article  PubMed  Google Scholar 

  • Zhou L, Lin Q, Wang P, Yao L, Leong K, Tan Z, Huang Z (2017) Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co-overexpressing BDNF and VEGF in a rat model of cardiac arrest-induced global cerebral ischemia. Cell Death Dis 8(5):e2774–e2774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank all the members of Shahid Mirghani Research Institute for their collaboration.

Funding

This work was supported by the Semnan University of Medical Sciences, Semnan, Iran [grant number A-10-377-2].

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Authors and Affiliations

  1. Clinical Research Center, Kashan University of Medical Sciences, Kashan, Iran

    Mansour Sayyah

  2. Department of Physical Education and Sport Sciences, Bojnourd Branch, Islamic Azad University, Bojnourd, Iran

    Mehdi Seydyousefi

  3. Department of Caching Education, Istanbul Esenyurt University, Istanbul, Turkey

    Abdorreza Eghbal Moghanlou

  4. Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, T1K 3M4, Canada

    Gerlinde A. S. Metz

  5. Department of Physical Education and Sport Sciences, Ilam University, Ilam, Iran

    Nabi Shamsaei

  6. Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Mohammad Hasan Faghfoori

  7. Food Safety Research Center (salt), Semnan University of Medical Sciences, Semnan, Iran

    Zeinab Faghfoori

  8. Department of Nutrition, School of Nutrition and Food Sciences, Semnan University of Medical Sciences, Semnan, Iran

    Zeinab Faghfoori

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  1. Mansour Sayyah
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  2. Mehdi Seydyousefi
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  3. Abdorreza Eghbal Moghanlou
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  4. Gerlinde A. S. Metz
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  6. Mohammad Hasan Faghfoori
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  7. Zeinab Faghfoori
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Contributions

MS has contributed to conceptualization, methodology and writing of original draft, MS, AEM and MHF contributed to investigation and methodology, GM has revised and editing the writing and ZF has contributed to supervision, funding acquisition, project administration. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zeinab Faghfoori.

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The authors stated that they have no conflicts of interest.

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The research protocol was approved by the Ethics Committee of University of Semnan Medical Sciences coded: IR. Semnan.Rec. 1397. 057.

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Sayyah, M., Seydyousefi, M., Moghanlou, A.E. et al. Activation of BDNF- and VEGF-mediated Neuroprotection by Treadmill Exercise Training in Experimental Stroke. Metab Brain Dis 37, 1843–1853 (2022). https://doi.org/10.1007/s11011-022-01003-7

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