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Molecular Neurobiology

, Volume 54, Issue 3, pp 1808–1817 | Cite as

Pharmacological Inhibition of PERK Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats Through the Activation of Akt

  • Feng Yan
  • Shenglong Cao
  • Jianru Li
  • Brandon Dixon
  • Xiaobo Yu
  • Jingyin Chen
  • Chi Gu
  • Wang Lin
  • Gao ChenEmail author
Article

Abstract

Neuronal apoptosis is a central pathological process in subarachnoid hemorrhage (SAH)-induced early brain injury. Endoplasmic reticulum (ER) stress was reported to have a vital role in the pathophysiology of neuronal apoptosis in the brain. The present study was designed to investigate the potential effects of ER stress and its downstream signals in early brain injury after SAH. One hundred thirty-four rats were subjected to an endovascular perforation model of SAH. The RNA-activated protein kinase-like ER kinase (PERK) inhibitor GSK2606414 and the Akt inhibitor MK2206 were injected intracerebroventricularly. SAH grade, neurologic scores, and brain water content were measured 72 h after subarachnoid hemorrhage. Expression of PERK and its downstream signals, Akt, Bcl-2, Bax, and cleaved caspase-3, were examined using Western blot analysis. Specific cell types that expressed PERK were detected with double immunofluorescence staining. Neuronal cell death was demonstrated with terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL). Our results showed that the expression of p-PERK and its downstream targets, p-eIF2α and ATF4, increased after SAH and peaked at 72 h after SAH. PERK was expressed mostly in neurons. The inhibition of PERK with GSK2606414 reduced p-PERK, p-eIF2α, and ATF4 expression. Furthermore, GSK2606414 treatment increased p-Akt levels and the Bcl-2/Bax ratio as well as decreased cleaved caspase-3 expression and neuronal death, thereby improving neurological deficits at 72 h after SAH. The selective Akt inhibitor MK2206 abolished the beneficial effects of GSK2606414. PERK, the major transducer of ER stress, is involved in neuronal apoptosis after SAH. The inhibition of PERK reduces early brain injury via Akt-related anti-apoptosis pathways. PERK may serve as a promising target for future therapeutic intervention.

Keywords

Subarachnoid hemorrhage Early brain injury Endoplasmic reticulum stress PERK Apoptosis 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81400951, No. 81571106)

Compliance with ethical standard

All procedures were approved by the ethics committee of Zhejiang University and followed the NIH guidelines for the Care and Use of Laboratory Animals.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Feng Yan
    • 1
  • Shenglong Cao
    • 1
  • Jianru Li
    • 1
  • Brandon Dixon
    • 2
  • Xiaobo Yu
    • 1
  • Jingyin Chen
    • 1
  • Chi Gu
    • 1
  • Wang Lin
    • 1
  • Gao Chen
    • 1
    Email author
  1. 1.Department of NeurosurgeryThe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
  2. 2.Department of Basic Sciences, Division of PhysiologyLoma Linda University, School of MedicineLoma LindaUSA

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