Journal of Molecular Neuroscience

, Volume 67, Issue 3, pp 353–363 | Cite as

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

  • Yan Zhuang
  • Hui Xu
  • Seidu A. Richard
  • Jie Cao
  • Haiying Li
  • Haitao Shen
  • Zhengquan Yu
  • Jian Zhang
  • Zhong WangEmail author
  • Xiang LiEmail author
  • Gang Chen


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.


Intracranial hemorrhage Secondary brain injury EPAC2 Apoptosis BIM p38 



intracerebral hemorrhage


secondary brain injury


exchange proteins directly activated by cAMP


terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling


Fluoro-Jade B






Funding Information

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).

Compliance with Ethical Standards

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.

Conflict of Interest

The authors declare that there are no conflicts of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurosurgery and Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Department of NeurosurgeryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
  3. 3.Department of NeurosurgeryThe Sixth People’s Hospital of NantongNantongChina
  4. 4.Department of ImmunologyJiangsu UniversityZhenjiangChina

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