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Preconditioning Exercise in Rats Attenuates Early Brain Injury Resulting from Subarachnoid Hemorrhage by Reducing Oxidative Stress, Inflammation, and Neuronal Apoptosis

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Abstract

Subarachnoid hemorrhage (SAH) is a catastrophic form of stroke responsible for significant morbidity and mortality. Oxidative stress, inflammation, and neuronal apoptosis are important in the pathogenesis of early brain injury (EBI) following SAH. Preconditioning exercise confers neuroprotective effects, mitigating EBI; however, the basis for such protection is unknown. We investigated the effects of preconditioning exercise on brain damage and sensorimotor function after SAH. Male rats were assigned to either a sham-operated (Sham) group, exercise (Ex) group, or no-exercise (No-Ex) group. After a 3-week exercise program, they underwent SAH by endovascular perforation. Consciousness level, neurological score, and sensorimotor function were studied. The expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), 4-hydroxynonenal (4HNE), nitrotyrosine (NT), ionized calcium-binding adaptor molecule 1 (Iba1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β), 14–3-3γ, p-β-catenin Ser37, Bax, and caspase-3 were evaluated by immunohistochemistry or western blotting. The terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) assay was also performed. After SAH, the Ex group had significantly reduced neurological deficits, sensorimotor dysfunction, and consciousness disorder compared with the No-Ex group. Nrf2, HO-1, and 14–3-3γ were significantly higher in the Ex group, while 4HNE, NT, Iba1, TNF-α, IL-6, IL-1β, Bax, caspase-3, and TUNEL-positive cells were significantly lower. Our findings suggest that preconditioning exercise ameliorates EBI after SAH. The expression of 4HNE and NT was reduced by Nrf2/HO-1 pathway activation; additionally, both oxidative stress and inflammation were reduced. Furthermore, preconditioning exercise reduced apoptosis, likely via the 14–3-3γ/p-β-catenin Ser37/Bax/caspase-3 pathway.

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Availability of Data and Material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Sushil Dawka, ELS, Andrea Baird, MD, and Bronwen Gardner, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.

Funding

This study was supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant Nos. JP16K10746 and JP20K11640 to Kiyoshi Kikuchi and JP20K19312 to Shotaro Otsuka), General Insurance Association of Japan (to Kiyoshi Kikuchi), ZENKYOREN (National Mutual Insurance Federation of Agricultural Cooperatives) of Japan (to Kiyoshi Kikuchi), Mitsui Sumitomo Insurance Welfare Foundation of Japan (to Kiyoshi Kikuchi), Descente and Ishimoto Memorial Foundation for the Promotion of Sports Science (to Kiyoshi Kikuchi), and Taiju Life Social Welfare Foundation (to Kiyoshi Kikuchi).

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Authors and Affiliations

  1. Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

    Shotaro Otsuka, Seiya Takada, Ikuro Maruyama & Kiyoshi Kikuchi

  2. Division of Laboratory Animal Science, Research Support Center, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

    Kentaro Setoyama

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

    Kazuki Nakanishi, Takuto Terashi, Kosuke Norimatsu, Akira Tani & Harutoshi Sakakima

  4. Division of Brain Science, Department of Physiology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, Fukuoka, 830-0011, Japan

    Eiichiro Tanaka & Kiyoshi Kikuchi

  5. Department of Pharmacology, Faculty of Dentistry, Mahidol University, 6 Rajthevee, Bangkok, 10400, Thailand

    Salunya Tancharoen

  6. Department of Neurosurgery, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, Fukuoka, 830-0011, Japan

    Kiyoshi Kikuchi

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  1. Shotaro Otsuka
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Shotaro Otsuka wrote the manuscript and performed the animal, histochemical, and biochemical studies. Kentaro Setoyama conducted the subarachnoid hemorrhage modeling in rats. Seiya Takada, Kazuki Nakanishi, Takuto Terashi, Kosuke Norimatsu, and Akira Tani performed the animal study and quantitative analysis. Harutoshi Sakakima conducted the histochemical and biochemical studies. Salunya Tancharoen conducted the animal study and wrote the manuscript. Ikuro Maruyama and Eiichiro Tanaka performed the literature review. Kiyoshi Kikuchi conducted the animal study, performed the literature review, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kiyoshi Kikuchi.

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The experimental protocol was approved by the ethics board of the Institute of Experimental Animal Science of Kagoshima University.

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Otsuka, S., Setoyama, K., Takada, S. et al. Preconditioning Exercise in Rats Attenuates Early Brain Injury Resulting from Subarachnoid Hemorrhage by Reducing Oxidative Stress, Inflammation, and Neuronal Apoptosis. Mol Neurobiol 58, 5602–5617 (2021). https://doi.org/10.1007/s12035-021-02506-7

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