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Protective Effects of Hyperbaric Oxygen Therapy on Brain Injury by Regulating the Phosphorylation of Drp1 Through ROS/PKC Pathway in Heatstroke Rats

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Abstract

This study aimed to elucidate the neurotherapeutic effect of hyperbaric oxygen (HBO) on brain injury and the potential role of dynamin-related protein 1 (Drp1) and its regulatory pathway in heatstroke (HS) rats. In in vivo experiments, rats were exposed to HBO after the onset of HS, or the same pressure but normal air as a control. The results indicated that HBO decreased the mortality and thermoregulatory dysfunction and prolonged the survival time of HS rats. Neurological dysfunction induced by HS was attenuated by HBO through assessment of modified neurological severity score and Morris water maze. HBO also alleviated histopathologic changes and oxidative injury (malondialdehyde and 8-hydroxyguanine), increased activities of superoxide dismutase (SOD) and glutathione/oxidized glutathione and ameliorated apoptotic parameters (caspase-3/6 activities and the number of apoptotic cells) of the hippocampus, hypothalamus and brain stem in rats compared to the HS group. Phosphorylation of DrpSer616 was increased by HS but decreased by HBO in the brains of rats determined by Western blot and immunohistochemical staining. In experiments in vitro, rat hippocampal neurons were used as a heat stress (HS) cellular model to examine the effects of HBO. As the results, HBO attenuated HS-induced cytotoxicity, oxidative injury (malondialdehyde), reactive oxygen species (ROS) generation, decreasing SOD activity and apoptosis. Drp1 inhibitor (Mdivi-1) treatment produced the same effects and had a trend to decrease oxidative injury. But the difference is not statistically significant. HBO and Mdivi-1decreased the phosphorylation of DrpSer616 induced by HS and HBO decreased the phosphorylation of protein kinase C (PKC) induced by HS. Moreover, both PKC inhibitor and ROS scavenger inhibited HS-induced p-DrpSer616. In conclusion, HBO may alleviate the brain injury caused by HS by decreasing ROS/PKC-regulated p-DrpSer616.

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Acknowledgements

I would like to extend my heartfelt thanks to Prof. Weigang Xu for his insightful guidance in the course of my experiments. I am also grateful to my baby who encouraged me to finish the experiments and the writing of this paper when he was infant.

Funding

This work was supported by grants from the Natural Science Foundation of Guangdong Province (s2013030013217), National Natural Science Foundation of China [NO. 81571940, 81741125] and the PLA Logistics Research Project of China [CWH17L020, 17CXZ008, 18CXZ030].

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Authors and Affiliations

  1. Department of Hyperbaric Oxygen Medicine, The First School of Clinical Medicine, Southern Medical University (General Hospital of Southern Theater Command of PLA), Guangzhou, Guangdong, China

    Xiao-xiao Ni & Rong-hao Yu

  2. Department of Gerontology, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong, China

    Jing Nie

  3. Department of Rehabilitation Medicine, Affiliated Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China

    Qiu-you Xie

  4. Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University (General Hospital of Southern Theater Command of PLA), Guangzhou, Guangdong, China

    Lei Su & Zhi-feng Liu

  5. Key Laboratory of Hot Zone Trauma Care and Tissue Repair of PLA, General Hospital of Southern Theatre Command of PLA, Guangzhou, Guangdong, China

    Lei Su & Zhi-feng Liu

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  1. Xiao-xiao Ni
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  2. Jing Nie
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  3. Qiu-you Xie
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  4. Rong-hao Yu
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  5. Lei Su
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  6. Zhi-feng Liu
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Contributions

XXN designed and performed the experiments and wrote the manuscript. ZFL helped design the experiments and wrote the manuscript. LS designed the experiments. JN helped perform experiments in vivo. QYX and RHY helped experiments using hyperbaric oxygen. In Figs. 1–6, XXN and ZFL generated the data and labeled the image. In Fig. 2–4, JN and QYX generated the histopathology, immune- histochemistry and TUNEL staining data. In Fig. 7, XXN and JN performed the graphing.

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Correspondence to Lei Su or Zhi-feng Liu.

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Research Involving Human Participants and/or Animals

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Ethics Committee for Animal Experiments of the General Hospital of Southern Theater Command of PLA [SYXK (粤) 2019-0100]. This article does not contain any studies with human participants performed by any of the authors.

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Ni, Xx., Nie, J., Xie, Qy. et al. Protective Effects of Hyperbaric Oxygen Therapy on Brain Injury by Regulating the Phosphorylation of Drp1 Through ROS/PKC Pathway in Heatstroke Rats. Cell Mol Neurobiol 40, 1253–1269 (2020). https://doi.org/10.1007/s10571-020-00811-8

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