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Human recombinant factor VIIa may improve heat intolerance in mice by attenuating hypothalamic neuronal apoptosis and damage

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Abstract

Intolerance to heat exposure is believed to be associated with hypothalamo-pituitary-adrenocortical (HPA) axis impairment [reflected by decreases in blood concentrations of both adrenocorticotrophic-hormone (ACTH) and corticosterone]. The purpose of this study was to determine the effect of human recombinant factor VIIa (rfVIIa) on heat intolerance, HPA axis impairment, and hypothalamic inflammation, ischemic and oxidative damage, and apoptosis in mice under heat stress. Immediately after heat stress (41.2 °C for 1 h), mice were treated with vehicle (1 mL/kg of body weight) or rfVIIa (65–270 µg/kg of body weight) and then returned to room temperature (26 °C). Mice still alive on day 4 of heat exposure were considered survivors. Cellular ischemia markers (e.g., glutamate, lactate-to-pyruvate ratio), oxidative damage markers (e.g., nitric oxide metabolite, hydroxyl radials), and pro-inflammatory cytokines (e.g., interleukin-6, interleukin-1β, tumor necrosis factor-α) in hypothalamus were determined. In addition, blood concentrations of both ACTH and corticosterone were measured. Hypothalamic cell damage was assessed by determing the neuronal damage scores, whereas the hypothalamic cell apoptosis was determined by assessing the numbers of cells stained with terminal deoxynucleotidyl transferase-mediated αUTP nick-end labeling, caspase-3-positive cells, and platelet endothelial cell adhesion molecula-1-positive cells in hypothalamus. Compared with vehicle-treated heated mice, rfVIIa-treated heated mice had significantly higher fractional survival (8/10 vs 1/10), lesser thermoregulatory deficit (34.1 vs 24.8 °C), lesser extents of ischemic, oxidative, and inflammatory markers in hypothalamus, lesser neuronal damage scores and apoptosis in hypothalamus, and lesser HPA axis impairment. Human recombinant factor VIIa appears to exert a protective effect against heatstroke by attenuating hypothalamic cell apoptosis (due to ischemic, inflammatory, and oxidative damage) in mice.

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Acknowledgments

This work was supported in part by Grants NSC99-2314-B-384-006-MY2, NSC99-2314-B-384-004-MY3, and NSC98-2314-B-218-MY2 from the Taiwan National Science Council; Grant DOH99-TD-B-111-003 from the Taiwan Department of Health; funds from the Taiwan Center of Excellence for Clinical Trials and Research in Neuroscience. We would like to thank four anonymous reviewers and the editor for their comments.

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The authors have no conflict of interest.

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Authors and Affiliations

  1. Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 112, Taiwan

    Chuan-Chih Hsu

  2. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, 710, Taiwan

    Sheng-Hsien Chen

  3. Da-An Hospital of Women and Children, Tainan, 712, Taiwan

    Sheng-Hsien Chen

  4. Meridigen Biotech Co., Ltd., Taipei, 114, Taiwan

    Cheng-Hsien Lin

  5. Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, Tainan, 710, Taiwan

    Cheng-Hsien Lin

  6. Department of Cardiovascular Surgery, School of Medicine, Taiwan Adventist Hospital, National Yang-Ming University, Taipei, Taiwan

    Ming-Chi Yung

  7. Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan

    Ming-Chi Yung

Authors
  1. Chuan-Chih Hsu
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  2. Sheng-Hsien Chen
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Corresponding authors

Correspondence to Cheng-Hsien Lin or Ming-Chi Yung.

Additional information

Chuan-Chih Hsu and Sheng-Hsien Chen have contributed equally to this work.

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Hsu, CC., Chen, SH., Lin, CH. et al. Human recombinant factor VIIa may improve heat intolerance in mice by attenuating hypothalamic neuronal apoptosis and damage. Apoptosis 19, 1484–1496 (2014). https://doi.org/10.1007/s10495-014-1020-1

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