Upregulating the Expression of Survivin-HBXIP Complex Contributes to the Protective Role of IMM-H004 in Transient Global Cerebral Ischemia/Reperfusion.

Abstract

IMM-H004, a 3-piperazinylcoumarin compound derived from coumarin, has been proved effective against CA1 cell loss and spatial learning impairments resulting from transient global ischemia/reperfusion (TGCI/R), while the mechanism is still largely unknown. Here, we confirmed that treatment of rats with IMM-H004 immediately after TGCI/R ameliorated delayed neuronal death (DND) in the CA1 of hippocampus and cortex. Further study suggested that IMM-H004 contributed to the expression of antiapoptotic protein survivin through the activation of PI3K-dependent protein kinase B (PKB/Akt), which led to the phosphorylation of forkhead box O1 (FoxO1), then relieved the inhibiting effect on survivin promoter. Additionally, IMM-H004 also enhanced the expression of hepatitis B X-interacting protein (HBXIP), which formed a complex with survivin to prevent the activation of caspase death cascade, thereby halting apoptotic cell death. Finally, we injected a HBXIP siRNA into hippocampus and performed microelectroporation before ischemia/reperfusion, which abolished the protective effect of IMM-H004. Further study revealed that HBXIP maintained the high expression of Akt and survivin. Collectively, our findings demonstrated that DND after TGCI/R was alleviated by IMM-H004 through promoting the formation of survivin-HBXIP complex, which further emphasized the importance of endogenous protein involved in self-repair after stroke.

• Authors: Shi-Feng Chu, Zhao Zhang, Wei Zhang, Mei-Jin Zhang, Yan Gao, Ning Han, Wei Zuo, Hui-Yong Huang, Nai-Hong Chen
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 54 Issue 1 Pg. 524-540 (01 2017) ISSN: 1559-1182 [Electronic] United States
• PMID: 26742528 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Birc5 protein, rat
• Coumarins
• IMM-H004
• LAMTOR5 protein, human
• Microtubule-Associated Proteins
• Neuroprotective Agents
• Survivin

Topics

• Adaptor Proteins, Signal Transducing (biosynthesis, genetics)
• Animals
• Coumarins (administration & dosage)
• Gene Expression
• Ischemic Attack, Transient (genetics, metabolism, prevention & control)
• Male
• Microtubule-Associated Proteins (biosynthesis, genetics)
• Neuroprotective Agents (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (genetics, metabolism, prevention & control)
• Survivin
• Up-Regulation (drug effects, physiology)