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Neuroprotective effect of meglumine cyclic adenylate against ischemia/reperfusion injury via STAT3-Ser727 phosphorylation

  • Author Footnotes
    1 Both authors contribute equally to this work.
    Xin-Qing Niu
    Footnotes
    1 Both authors contribute equally to this work.
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Author Footnotes
    1 Both authors contribute equally to this work.
    Dong-Dong Li
    Footnotes
    1 Both authors contribute equally to this work.
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Ya-Jun Bao
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Qi Yang
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Ying-Kui Liu
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Feng Lu
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Jing-Zhi Yan
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Xiao-Hui Yin
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
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  • Chong Li
    Correspondence
    Corresponding author at: Jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Jiangsu 221004, China.
    Affiliations
    jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China

    Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China
    Search for articles by this author
  • Author Footnotes
    1 Both authors contribute equally to this work.

      Highlights

      • Meglumine cyclic adenylate protects neurons against ischemia/reperfusion injury.
      • Meglumine cyclic adenylate induces mitochondria translocation of STAT3.
      • Meglumine cyclic adenylate induces inhibition of apoptosis pathway.

      Abstract

      Objectives

      Ischemia/reperfusion can induce neuronal apoptosis in the brain and lead to function deficits. The activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is neuroprotective against transient cerebral ischemia. The neuroprotective mechanisms of PKA mainly involve the regulation of gene transcription via the PKA/CREB pathway. The present study aims to investigate the neuroprotective effect of meglumine cyclic adenylate, an activator of PKA, under a rat model of global cerebral ischemia/reperfusion and to reveal the underlying mechanism involving signal transducer and activator of transcription 3 (STAT3)-Ser727 phosphorylation and mitochondrion modulation.

      Materials and methods

      Male Sprague-Dawley rats were subjected to 15 min global cerebral ischemia, and meglumine cyclic adenylate was treated through tail intravenous injection 30 min before ischemia. Cresyl violet staining was used to evaluate neuron injury at 5 d of reperfusion. Western blotting was used to detect p-Ser727-STAT3, total STAT3, cytochrome c (Cyt c) and active caspase-3 in the tissues of hippocampal CA1 region at 6 h of reperfusion. STAT3-S727A was overexpressed in HT22 cells to reveal the significance of STAT3-Ser727 phosphorylation in the neuroprotective effect of meglumine cyclic adenylate.

      Results

      Pretreatment with meglumine cyclic adenylate not only significantly ameliorated neuron loss in CA1 region after global cerebral ischemia but also enhanced STAT3-Ser727 phosphorylation, increased mitochondrial STAT3, and decreased cytosolic Cyt c and active caspase-3. Overexpression of STAT3-S727A in HT22 cells eliminated meglumine cyclic adenylate-induced increase of p-Ser727-STAT3, mitochondrial STAT3, cytosolic Cyt c and active caspase-3.

      Conclusion

      Meglumine cyclic adenylate protects neurons against ischemia/reperfusion injury via promoting p-Ser727-STAT3-associated mitochondrion modulation and inhibiting apoptosis pathway.

      Keywords

      Abbreviations:

      signal transducer and activator of transcription 3 (STAT3), cAMP-dependent protein kinase (PKA), reactive oxygen species (ROS), mitochondrial permeability transition pore (MPTP), Janus kinases (JAKs), G protein-coupled receptors (GPCRs), ischemia/reperfusion (I/R), electron transport chain (ETC)
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