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Effects of detraining on preconditioning exercise-induced neuroprotective potential after ischemic stroke in rats

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Abstract

Preconditioning exercise prior to stroke exerts neuroprotection, which is an endogenous strategy that leads the brain cells to express several intrinsic factors and inhibits their apoptosis. However, it is unclear how long these benefits last after exercise cessation. The aim of this study was to investigate the effects of detraining on preconditioning exercise-induced neuroprotective potential after stroke. Rats were trained using a treadmill for aerobic exercise 5 days each week for 3 weeks, and their neuroprotective effects were examined until 3 weeks after exercise cessation. Stroke was induced by 60 min of left middle cerebral artery occlusion at 3 days, 1, 2, and 3 weeks after exercise cessation. Infarct volume, neurological deficits, sensorimotor function, expression levels of brain-derived neurotrophic factor (BDNF), hypoxia-induced factor-1α (HIF-1α), glial fibrillary acidic protein (GFAP), and P2X7 receptors, and apoptosis activity were examined using immunohistochemical and western blot analyses. Preconditioning exercise significantly reduced infarct volume and ameliorated sensorimotor function after stroke, and its beneficial effects were observed until 2 weeks after exercise cessation. The expression level of BDNF in the ischemic brain was significantly upregulated at 3 days after exercise cessation; however, the expression levels of HIF-1α, GFAP, and P2X7 receptor were significantly increased until 2 weeks after exercise cessation; thereby, significant anti-apoptotic effects were lost at 3 weeks of detraining. Our findings suggest that preconditioning exercise-induced neuroprotective potential may be lost shortly after exercise cessation. Neuroprotection through intrinsic protective factors, such as BDNF and HIF-1α, may provide different neuroprotective mechanisms in a time-dependent manner during detraining.

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Data availability

Available from the corresponding author upon reasonable request.

Abbreviations

BDNF:

Brain-derived neurotrophic factor

NGF:

Nerve growth factor

MCAO:

Middle cerebral artery occlusion

HIF-1α:

Hypoxia-induced factor-1α

TTC:

2,3,5–Triphenyltetrazorlium chloride

GFAP:

Glial fibrillary acidic protein

Bax:

Anti-B-cell lymphoma 2-associated X protein

References

  • Adlard PA, Perreau VM, Engesser-Cesar C, Cotman CW (2004) The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise. Neurosci Lett 363(1):43–48

    Article  CAS  Google Scholar 

  • Bocalini DS, Carvalho EV, de Sousa AF, Levy RF, Tucci PJ (2010) Exercise training-induced enhancement in myocardial mechanics is lost after 2 weeks of detraining in rats. Eur J Appl Physiol 109(5):909–914

    Article  Google Scholar 

  • Deplanque D, Masse I, Libersa C, Leys D, Bordet R (2012) Previous leisure-time physical activity dose dependently decreases ischemic stroke severity. Stroke Res Treat 2012:614925

    PubMed  Google Scholar 

  • Di Raimondo D, Rizzo G, Musiari G, Tuttolomondo A, Pinto A (2020) Role of regular physical activity in neuroprotection against acute ischemia. Int J Mol Sci 21(23):9086

    Article  Google Scholar 

  • Ding Y, Li J, Luan X, Ding YH, Lai Q, Rafols JA, Phillis JW, Clark JC, Diaz FG (2004) Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience 124(3):583–591

    Article  CAS  Google Scholar 

  • Dong Y, Zhao R, Chen XQ, Yu AC (2010) 14-3-3gamma and neuroglobin are new intrinsic protective factors for cerebral ischemia. Mol Neurobiol 41(2–3):218–231

    Article  CAS  Google Scholar 

  • Hirayama Y, Koizumi S (2017) Hypoxia-independent mechanisms of HIF-1α expression in astrocytes after ischemic preconditioning. Glia 65(3):523–530

    Article  Google Scholar 

  • Hirayama Y, Ikeda-Matsuo Y, Notomi S, Enaida H, Kinouchi H, Koizumi S (2015) Astrocyte-mediated ischemic tolerance. J Neurosci 35(9):3794–3805

    Article  CAS  Google Scholar 

  • Ho VM, Lee JA, Martin KC (2011) The cell biology of synapticity. Science 334(6056):623–628

    Article  CAS  Google Scholar 

  • Huang AM, Jen CJ, Chen HF, Yu L, Kuo YM, Chen HI (2006) Compulsive exercise acutely upregulates rat hippocampal brain-derived neurotrophic factor. J Neural Transm (vienna) 113(7):803–811

    Article  CAS  Google Scholar 

  • Islam MR, Young MF, Wrann CD (2017) Neuroprotective potential of exercise preconditioning in stroke. Cond Med 1(1):27–34

    PubMed  PubMed Central  Google Scholar 

  • Kim DH, Zhao X (2005) BDNF protects neurons following injury by modulation of caspase activity. Neurocrit Care 3(1):71–76

    Article  CAS  Google Scholar 

  • Kramer M, Dang J, Baertling F, Denecke B, Clarner T, Kirsch C, Beyer C, Kipp M (2010) TTC staining of damaged brain areas after MCA occlusion in the rat does not constrict quantitative gene and protein analyses. J Neurosci Methods 187(1):84–89

    Article  Google Scholar 

  • Kramer SF, Hung SH, Brodtmann A (2019) The impact of physical activity before and after stroke on stroke risk and recovery: a narrative review. Curr Neurol Neurosci Rep 19(6):28

    Article  Google Scholar 

  • Krarup LH, Truelsen T, Gluud C, Andersen G, Zeng X, Kõrv J, Oskedra A, Boysen G, ExStroke Pilot Trial Group (2008) Prestroke physical activity is associated with severity and long-term outcome from first-ever stroke. Neurology 71(17):1313–1318

    Article  Google Scholar 

  • Mujika I, Padilla S (2000) Detraining: loss of training-induced physiological and performance adaptations. Part I: short term insufficient training stimulus. Sports Med 30(2):79–87

    Article  CAS  Google Scholar 

  • Nakanishi K, Sakakima H, Norimatsu K, Otsuka S, Takada S, Tani A, Kikuchi K (2021) Effect of low-intensity motor balance and coordination exercise on cognitive functions, hippocampal Aβ deposition, neuronal loss, neuroinflammation, and oxidative stress in a mouse model of Alzheimer’s disease. Exp Neurol 337:113590

    Article  CAS  Google Scholar 

  • Otsuka S, Sakakima H, Sumizono M, Takada S, Terashi T, Yoshida Y (2016) The neuroprotective effects of preconditioning exercise on brain damage and neurotrophic factors after focal brain ischemia in rats. Behav Brain Res 303:9–18

    Article  CAS  Google Scholar 

  • Otsuka S, Sakakima H, Terashi T, Takada S, Nakanishi K, Kikuchi K (2019) Preconditioning exercise reduces brain damage and neuronal apoptosis through enhanced endogenous 14-3-3γ after focal brain ischemia in rats. Brain Struct Funct 224(2):727–738

    Article  CAS  Google Scholar 

  • Ploughman M, Windle V, MacLellan CL, White N, Doré JJ, Corbett D (2009) Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke 40:1490–1495

    Article  CAS  Google Scholar 

  • Ploughman M, Austin MW, Glynn L, Corbett D (2015) The effects of poststroke aerobic exercise on neuroplasticity: a systematic review of animal and clinical studies. Transl Stroke Res 6(1):13–28

    Article  Google Scholar 

  • Radak Z, Toldy A, Szabo Z, Siamilis S, Nyakas C, Silye G, Jakus J, Goto S (2006) The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neurochem Int 49(4):387–392

    Article  CAS  Google Scholar 

  • Ricciardi AC, López-Cancio E, Pérez de la Ossa N, Sobrino T, Hernández-Pérez M, Gomis M, Munuera J, Muñoz L, Dorado L, Millán M, Dávalos A, Arenillas JF (2014) Prestroke physical activity is associated with good functional outcome and arterial recanalization after stroke due to a large vessel occlusion. Cerebrovasc Dis 37(4):304–311

    Article  Google Scholar 

  • Sakakima H (2019) Endogenous neuroprotective potential due to preconditioning exercise in stroke. Phys Ther Res 22(2):45–52

    Article  Google Scholar 

  • Sakakima H, Khan M, Dhammu TS, Shunmugavel A, Yoshida Y, Singh I, Singh AK (2012) Stimulation of functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat model of transientcerebral ischemia and reperfusion. Restor Neurol Neurosci 30(5):383–396

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stroud N, Mazwi TM, Case LD, Brown RD Jr, Brott TG, Worrall BB, Meschia JF, Ischemic Stroke Genetics Study Investigators (2009) Prestroke physical activity and early functional status after stroke. J Neurol Neurosurg Psychiatry 80(9):1019–1022

    Article  CAS  Google Scholar 

  • Terashi T, Otsuka S, Takada S, Nakanishi K, Ueda K, Sumizono M, Kikuchi K, Sakakima H (2019) Neuroprotective effects of different frequency preconditioning exercise on neuronal apoptosis after focal brain ischemia in rats. Neurol Res 41(6):510–518

    Article  CAS  Google Scholar 

  • Tolppanen AM, Solomon A, Kulmala J, Kåreholt I, Ngandu T, Rusanen M, Laatikainen T, Soininen H, Kivipelto M (2015) Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia. Alzheimers Dement 11(4):434-443.e6

    Article  Google Scholar 

  • Waring CD, Henning BJ, Smith AJ, Nadal-Ginard B, Torella D, Ellison GM (2015) Cardiac adaptations from 4 weeks of intensity-controlled vigorous exercise are lost after a similar period of detraining. Physiol Rep 3(2):e12302

    Article  Google Scholar 

  • Yang J, Liu C, Du X, Liu M, Ji X, Du H, Zhao H (2018) Hypoxia inducible factor 1α plays a key role in remote ischemic preconditioning against stroke by modulating inflammatory responses in rats. J Am Heart Assoc 7(5):e007589

    Article  Google Scholar 

  • Yang T, Sun Y, Li Q, Li S, Shi Y, Leak RK, Chen J, Zhang F (2020) Ischemic preconditioning provides long-lasting neuroprotection against ischemic stroke: The role of Nrf2. Exp Neurol 325:113142

    Article  CAS  Google Scholar 

  • Zhang F, Wu Y, Jia J (2011) Exercise preconditioning and brain ischemic tolerance. Neuroscience 177:170–176

    Article  CAS  Google Scholar 

  • Zhang Q, Zhang L, Yang X, Wan Y, Jia J (2014) The effects of exercise preconditioning on cerebral blood flow change and endothelin-1 expression after cerebral ischemia in rats. J Stroke Cerebrovasc Dis 23(6):1696–1702

    Article  Google Scholar 

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Acknowledgements

The authors would like to thank Mr. Yuki Itashiki and Mr. Keita Fukumaru for their assistance in this animal study.

Funding

This work was supported by grants from JSPS KAKENHI (Grant No. JP20H0403 to Harutoshi Sakakima and Grant No. JP19K24315 to Shotaro Otsuka).

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Authors and Affiliations

  1. Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Japan

    Shotaro Otsuka, Seiya Takada & Ikuro Maruyama

  2. Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8544, Japan

    Harutoshi Sakakima, Akira Tani, Kazuki Nakanishi & Kosuke Norimatsu

  3. Department of Rehabilitation Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan

    Hiroshi Maejima

Authors
  1. Shotaro Otsuka
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  2. Harutoshi Sakakima
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  3. Akira Tani
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  4. Kazuki Nakanishi
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  5. Seiya Takada
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  6. Kosuke Norimatsu
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  7. Hiroshi Maejima
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  8. Ikuro Maruyama
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Contributions

All authors contributed to this study. This study is based on the original ideas of HS, SO, HM, and IM. SO, AT, ST, KN (Kazuki Nakanishi), and KN (Kosuke Norimatsu) performed the experiments and carried out the animal, histochemical and biochemical studies, as well as the quantitative analysis. HS and SO performed the literature review and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Harutoshi Sakakima.

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The authors declare no competing financial interests.

Ethical approval

The experimental protocol was approved by the Ethics Board of the Institute of Laboratory Animal Sciences of Kagoshima University.

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Otsuka, S., Sakakima, H., Tani, A. et al. Effects of detraining on preconditioning exercise-induced neuroprotective potential after ischemic stroke in rats. Brain Struct Funct 226, 2169–2180 (2021). https://doi.org/10.1007/s00429-021-02317-5

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  • DOI: https://doi.org/10.1007/s00429-021-02317-5

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