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The PERK Pathway Plays a Neuroprotective Role During the Early Phase of Secondary Brain Injury Induced by Experimental Intracerebral Hemorrhage

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Subarachnoid Hemorrhage

Part of the book series: Acta Neurochirurgica Supplement ((NEUROCHIRURGICA,volume 127))

Abstract

The protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, which is a branch of the unfolded protein response, participates in a range of pathophysiological processes of neurological diseases. However, few studies have investigated the role of the PERK in intracerebral hemorrhage (ICH). The present study evaluated the role of the PERK pathway during the early phase of ICH-induced secondary brain injury (SBI) and its potential mechanisms. An autologous whole blood ICH model was established in rats, and cultured primary cortical neurons were treated with oxyhemoglobin to mimic ICH in vitro. We found that levels of phosphorylated alpha subunit of eukaryotic translation initiation factor 2 (p-eIF2α) and activating transcription factor 4 (ATF4) increased significantly and peaked at 12 h during the early phase of the ICH. To further elucidate the role of the PERK pathway, we assessed the effects of the PERK inhibitor, GSK2606414, and the eIF2α dephosphorylation antagonist, salubrinal, at 12 h after ICH both in vivo and in vitro. Inhibition of PERK with GSK2606414 suppressed the protein levels of p-eIF2α and ATF4, resulting in increase of transcriptional activator CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase-12, which promoted apoptosis and reduced neuronal survival. Treatment with salubrinal yielded opposite results, which suggested that activation of the PERK pathway could promote neuronal survival and reduce apoptosis. In conclusion, the present study has demonstrated the neuroprotective effects of the PERK pathway during the early phase of ICH-induced SBI. These findings highlight the potential value of PERK pathway as a therapeutic target for ICH.

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Acknowledgments

This work was supported by the Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), Jiangsu Provincial Medical Youth Talent (No. QNRC2016728), Suzhou Key Medical Centre (No. Szzx201501), Scientific Department of Jiangsu Province (No. BE2017656), Suzhou Government (No. SYS201608 and LCZX201601), Jiangsu Province (No. 16KJB320008), and Zhangjiagang Science and Technology Pillar Program (ZKS1712).

Conflict of Interest: We declare that we have no conflicts of interest.

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Author notes

  1. Juyi Zhang & Peng Zhang

    Present address: Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China

  2. #These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China

    Chengjie Meng, Haiying Li, Haitao Shen, Zhong Wang, Xiang Li & Gang Chen

  2. Department of Neurosurgery, Yancheng First People’s Hospital, Yancheng, China

    Chengjie Meng

  3. Department of Rehabilitation Medicine, Zhangjiagang Hospital of Traditional Chinese Medicine, Suzhou, China

    Baoqi Dang

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  1. Juyi Zhang
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Correspondence to Xiang Li .

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Editors and Affiliations

  1. Department of Anethesiology, Loma Linda University Medical Center, Loma Linda, CA, USA

    Robert D. Martin

  2. Department of Neurosurgery, Loma Linda University Medical Center, Loma Linda, CA, USA

    Warren Boling

  3. Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou, China

    Gang Chen

  4. Department of Anesthesiology and Physiology, Loma Linda University Medical Center, Loma Linda, CA, USA

    John H. Zhang

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Zhang, J. et al. (2020). The PERK Pathway Plays a Neuroprotective Role During the Early Phase of Secondary Brain Injury Induced by Experimental Intracerebral Hemorrhage. In: Martin, R., Boling, W., Chen, G., Zhang, J. (eds) Subarachnoid Hemorrhage. Acta Neurochirurgica Supplement, vol 127. Springer, Cham. https://doi.org/10.1007/978-3-030-04615-6_17

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  • DOI: https://doi.org/10.1007/978-3-030-04615-6_17

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