Neuroprotection of Sevoflurane Against Ischemia/Reperfusion-Induced Brain Injury Through Inhibiting JNK3/Caspase-3 by Enhancing Akt Signaling Pathway.

Abstract

In this study, we investigated the neuroprotective effect of sevoflurane against ischemic brain injury and its underlying molecular mechanisms. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with sevoflurane alone or sevoflurane combined with LY294002/wortmannin (selective inhibitor of PI3K) before ischemia. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting and immunoprecipitation were performed to measure the phosphorylation of Akt1, PRAS40, ASK1, and JNK3 and the expression of cleaved-caspase-3. The results demonstrated that a moderate dose of sevoflurane inhalation of 2% for 2 h had significant neuroprotective effects against ischemia/reperfusion induced hippocampal neuron death. Sevoflurane significantly increased Akt and PRAS40 phosphorylation and decreased the phosphorylation of ASK1 at 6 h after reperfusion and the phosphorylation of JNK3 at 3 days after reperfusion following 15 min of transient global brain ischemia. Conversely, LY294002 and wortmannin significantly inhibited the effects of sevoflurane. Taken together, the results suggest that sevoflurane could suppress ischemic brain injury by downregulating the activation of the ASK1/JNK3 cascade via increasing the phosphorylation of Akt1 during ischemia/reperfusion.

• Authors: Xiang-Ru Wen, Yan-Yan Fu, Hong-Zhi Liu, Jian Wu, Xiao-Ping Shao, Xun-Bao Zhang, Man Tang, Yue Shi, Kai Ma, Fang Zhang, Yi-Wen Wang, Hui Tang, Dong Han, Pu Zhang, Shu-Ling Wang, Zhou Xu, Yuan-Jian Song
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 53 Issue 3 Pg. 1661-1671 (Apr 2016) ISSN: 1559-1182 [Electronic] United States
• PMID: 25687432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Chromones
• Methyl Ethers
• Morpholines
• Neuroprotective Agents
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Sevoflurane
• Mitogen-Activated Protein Kinase 10
• MAP Kinase Kinase Kinase 5
• Caspase 3
• Wortmannin

Topics

• Androstadienes (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Brain Injuries (complications, drug therapy, enzymology, pathology)
• CA1 Region, Hippocampal (drug effects, pathology)
• Caspase 3 (metabolism)
• Chromones (pharmacology, therapeutic use)
• Enzyme Activation (drug effects)
• MAP Kinase Kinase Kinase 5 (metabolism)
• Male
• Methyl Ethers (pharmacology, therapeutic use)
• Mitogen-Activated Protein Kinase 10 (metabolism)
• Models, Biological
• Morpholines (pharmacology, therapeutic use)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotection (drug effects)
• Neuroprotective Agents (pharmacology)
• Phosphorylation (drug effects)
• Rats, Sprague-Dawley
• Reperfusion Injury (complications, drug therapy, enzymology, pathology)
• Sevoflurane
• Signal Transduction (drug effects)
• Wortmannin