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Brain Structure and Function

, Volume 224, Issue 2, pp 727–738 | Cite as

Preconditioning exercise reduces brain damage and neuronal apoptosis through enhanced endogenous 14-3-3γ after focal brain ischemia in rats

  • Shotaro Otsuka
  • Harutoshi SakakimaEmail author
  • Takuto Terashi
  • Seiya Takada
  • Kazuki Nakanishi
  • Kiyoshi KikuchiEmail author
Original Article
  • 249 Downloads

Abstract

14-3-3γ is an important early ischemia-inducible protective factor against ischemic cell death in cerebral cortical neurons. We investigated the anti-apoptosis mechanism of enhanced 14-3-3γ mediated by preconditioning exercise-induced brain ischemic tolerance after stroke. Rats were assigned to four groups: exercise and ischemia (Ex group), ischemia and no exercise (No-Ex group), exercise and no ischemia (Ex-only group), and no exercise and ischemia (control group). Rats were trained on a treadmill for 5 days a week for 3 weeks (running speed, 25 m/min; running duration, 30 min/day). After the exercise program, stroke was induced by left middle cerebral artery occlusion. The infarct volume, neurological deficits, and motor function, as well as expression levels of hypoxia-induced factor-1α (HIF-1α), 14-3-3γ, P2X7 receptors, p-β-catenin Ser37, Bax, and caspase 3 were evaluated by immunohistochemistry and western blotting. The expression of HIF-1α and 14-3-3γ significantly increased in neurons and astrocytes in the Ex-only group. HIF-1α was co-expressed with P2X7 receptor- and GFAP-positive astrocytes. After stroke, the Ex group had significantly reduced brain infarction. HIF-1α and 14-3-3γ significantly increased in the Ex group compared to the No-Ex group. In addition, p-β-catenin Ser37 significantly increased following elevated 14-3-3γ; in contrast, Bax and caspase 3 were significantly reduced in the Ex group. Our findings suggest that preconditioning exercise prior to ischemia induces neuron- and astrocyte-mediated brain ischemic tolerance through increased expression of HIF-1α and 14-3-3γ, which are intrinsic protective factors; the upregulated 14-3-3γ induced by preconditioning exercise reduces ischemic neuronal cell death through the 14-3-3γ/p-β-catenin Ser37/Bax/caspase 3 anti-apoptotic pathway.

Keywords

14-3-3γ HIF-1α Physical activity Ischemic tolerance Intrinsic factor 

Notes

Acknowledgements

The authors greatly appreciate the assistance of Ms. Megumi Sumizono and Mr. Koki Ueda, and are grateful to Ms. Hui Gao for excrement technical assistance. This work was supported by grant from the JSPS KAKENHI (Grant no. JP17K01459 to Harutoshi Sakakima). This study was supported by grants from the JSPS KAKENHI (Grant no. JP16K10746 to Kiyoshi Kikuchi), General Insurance Association of Japan (to Kiyoshi Kikuchi), ZENKYOREN (National Mutual Insurance Federation of Agricultural Cooperatives) of Japan (to Kiyoshi Kikuchi), and Mitsui Sumitomo Insurance Welfare Foundation of Japan (to Kiyoshi Kikuchi).

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Ethical approval

All experiments were performed according to national and institutional guidelines and were approved by the appropriate authority.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018
corrected publication 2018

Authors and Affiliations

  • Shotaro Otsuka
    • 1
  • Harutoshi Sakakima
    • 1
    Email author
  • Takuto Terashi
    • 1
  • Seiya Takada
    • 1
  • Kazuki Nakanishi
    • 1
  • Kiyoshi Kikuchi
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Course of Physical Therapy, School of Health Sciences, Faculty of MedicineKagoshima UniversityKagoshimaJapan
  2. 2.Division of Brain Science, Department of PhysiologyKurume University School of MedicineKurumeJapan
  3. 3.Department of NeurosurgeryKurume University School of MedicineKurumeJapan
  4. 4.Department of Systems Biology in ThromboregulationKagoshima University Graduate School of Medical and Dental ScienceKagoshimaJapan
  5. 5.Department of Pharmacology, Faculty of DentistryMahidol UniversityBangkokThailand

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