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

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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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81274122, No. 81102831, No. 81173578), the National Key Sci-Tech Major Special Item (No. 2012ZX09301002-004, No. 2012ZX09103101-006), the National High-Tech R&D Program (863 Program) (No. 2012AA020303), the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) (No. IRT1007), the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20121106130001), the Beijing Natural Science Foundation (No. 7131013, No. 7142115), and the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (No. BZ0150).

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Correspondence to Nai-Hong Chen.

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Zhao Zhang contributed equally to this work.

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Chu, SF., Zhang, Z., Zhang, W. et al. Upregulating the Expression of Survivin-HBXIP Complex Contributes to the Protective Role of IMM-H004 in Transient Global Cerebral Ischemia/Reperfusion. Mol Neurobiol 54, 524–540 (2017). https://doi.org/10.1007/s12035-015-9673-5

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  • DOI: https://doi.org/10.1007/s12035-015-9673-5

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