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

• Published in: Journal of molecular neuroscience 2019-03, Vol.67 (3), p.353-363
• Main Authors: Zhuang, Yan, Xu, Hui, Richard, Seidu A., Cao, Jie, Li, Haiying, Shen, Haitao, Yu, Zhengquan, Zhang, Jian, Wang, Zhong, Li, Xiang, Chen, Gang
• Format: Article
• Language: English
• Subjects: Activation; Animal models; Animals; Apoptosis; Bcl-2 protein; Bcl-2-Like Protein 11 - metabolism; Benzene Derivatives - pharmacology; BIM protein; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - metabolism; Brain injury; Caspase; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cells, Cultured; Computer simulation; Cortex; Cyclic AMP; Guanine Nucleotide Exchange Factors - antagonists & inhibitors; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Head injuries; Hemorrhage; Inhibition; Intracranial Hemorrhages - metabolism; Kinases; Male; Neurochemistry; Neurological diseases; Neurology; Neurosciences; Oxyhemoglobin; p38 Mitogen-Activated Protein Kinases - metabolism; Pathogenesis; Protein expression; Proteins; Proteomics; Rats; Rats, Sprague-Dawley; Signal Transduction; Signaling; Sulfones - pharmacology; Traumatic brain injury
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-018-1215-y

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.