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Inhibition of EPAC2 Attenuates Intracerebral Hemorrhage-Induced Secondary Brain Injury via the p38/BIM/Caspase-3 Pathway

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Abstract

Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway intermediaries that have been implicated in the pathogenesis of several human diseases, particularly neurological disorders. However, their pathogenic role in secondary brain injury (SBI) induced by intracranial hemorrhage (ICH) is unknown. The aim of this study was to examine the effects of EPAC2 on ICH-induced SBI and its underlying mechanisms. An in vivo ICH model was established in Sprague–Dawley rats by autologous blood injection. In addition, rat primary cortical neuronal cultures were exposed to oxyhemoglobin to simulate ICH in vitro. The function of EPAC2 in SBI induced by ICH was studied using the EPAC2-specific inhibitor ESI-05. In this study, we found that EPAC2 protein expression was significantly increased in the ICH models in vitro and in vivo. Furthermore, EPAC2 activation was inhibited by ESI-05 under ICH conditions. Inhibition of EPAC2 decreased the apoptosis rate of nerve cells in the cortex accompanied by a corresponding decrease in the protein expression of phosphorylated p38, Bcl-2-like protein 11 (BIM), and caspase-3. In summary, this study showed that inhibition of EPAC2 activation by ESI-05 suppressed SBI induced by ICH via the p38/BIM/caspase-3 signaling pathway.

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Abbreviations

ICH:

intracerebral hemorrhage

SBI:

secondary brain injury

EPAC2:

exchange proteins directly activated by cAMP

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

FJB:

Fluoro-Jade B

SD:

Sprague–Dawley

OxyHb:

oxyhemoglobin

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Funding

This work was supported by the Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), Suzhou Key Medical Center (No. Szzx201501), Scientific Department of Jiangsu Province (No. BE2017656), Natural Science Foundation of Jiangsu Province (No. BK20180204), Suzhou Government (No. LCZX201601), and grants from the National Natural Science Foundation of China (No. 81571121, No. 81801151 and No. 81771252).

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Author notes

  1. Yan Zhuang and Hui Xu 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, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, China

    Yan Zhuang, Hui Xu, Jie Cao, Haiying Li, Haitao Shen, Zhengquan Yu, Jian Zhang, Zhong Wang, Xiang Li & Gang Chen

  2. Department of Neurosurgery, The Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, Jiangsu Province, China

    Yan Zhuang

  3. Department of Neurosurgery, The Sixth People’s Hospital of Nantong, No. 500 Yonghe Road, Nantong, 226011, Jiangsu Province, China

    Hui Xu

  4. Department of Immunology, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu Province, China

    Seidu A. Richard

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  1. Yan Zhuang
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Correspondence to Zhong Wang or Xiang Li.

Ethics declarations

All experiments were approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (Suzhou, China). The experimental procedures were conducted strictly according to the Animal Health Management Committee of Soochow University. In accordance with their animal ethics criteria, the sample size of this study was determined by efficacy analysis.

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Zhuang, Y., Xu, H., Richard, S.A. et al. Inhibition of EPAC2 Attenuates Intracerebral Hemorrhage-Induced Secondary Brain Injury via the p38/BIM/Caspase-3 Pathway. J Mol Neurosci 67, 353–363 (2019). https://doi.org/10.1007/s12031-018-1215-y

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