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<p>HMGB1-mediated neuroinflammation assumes a pivotal position in the pathophysiological framework of a multitude of neurological disorders, including ischemic stroke, which still urgently need effective therapeutic agents. CDDO-Me, is a potentially useful therapeutic drug for diabetic nephropathy, whereas the neuroprotective properties and underlying mechanism in ischemic stroke have not been reported as yet. In the present study, CDDO-Me was found to alleviate OGD/R induced nerve cell injury and protect the cerebral ischemia of rats. In addition, the proinflammatory activity of HMGB1 was inhibited by CDDO-Me through directly binding to HMGB1 and then disrupting its interaction with receptor TLR4. The binding affinity of CDDO-Me to HMGB1 was 117 µM indicated by surface plasmon resonance (SPR) assay. On this basis, we observed that CDDO-Me could slightly change the secondary and steric conformation as well as the thermal stability of HMGB1. Subsequently, molecular dynamics (MD) simulation showed that CDDO-Me mainly binds to the A-box domain of HMGB1, which was maintained by weak interaction forces like van der Waals and hydrophobicity. Further virtual mutagenesis and binding free energy calculations identified F38 and F89 in the A-box as key residues involved in HMGB1-CDDO-Me interaction. These findings indicated that CDDO-Me can improve stroke-induced inflammatory damage through direct binding HMGB1 and negative regulation of HMGB1-TLR4 downstream cytokine signaling activity.</p> Graphical Abstract <p></p>

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Investigating the Potential of CDDO-Me as an HMGB1 Inhibitor in Mitigating Cerebral Ischemia-Reperfusion Injury

  • 期刊论文

  • 发表日期：

    2025年10月27日

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  • Libang Zhang,
  • Guolong Li,
  • Xingru Chen,
  • Tian Li,
  • Richa Raj,
  • Pingping Shen

摘要

HMGB1-mediated neuroinflammation assumes a pivotal position in the pathophysiological framework of a multitude of neurological disorders, including ischemic stroke, which still urgently need effective therapeutic agents. CDDO-Me, is a potentially useful therapeutic drug for diabetic nephropathy, whereas the neuroprotective properties and underlying mechanism in ischemic stroke have not been reported as yet. In the present study, CDDO-Me was found to alleviate OGD/R induced nerve cell injury and protect the cerebral ischemia of rats. In addition, the proinflammatory activity of HMGB1 was inhibited by CDDO-Me through directly binding to HMGB1 and then disrupting its interaction with receptor TLR4. The binding affinity of CDDO-Me to HMGB1 was 117 µM indicated by surface plasmon resonance (SPR) assay. On this basis, we observed that CDDO-Me could slightly change the secondary and steric conformation as well as the thermal stability of HMGB1. Subsequently, molecular dynamics (MD) simulation showed that CDDO-Me mainly binds to the A-box domain of HMGB1, which was maintained by weak interaction forces like van der Waals and hydrophobicity. Further virtual mutagenesis and binding free energy calculations identified F38 and F89 in the A-box as key residues involved in HMGB1-CDDO-Me interaction. These findings indicated that CDDO-Me can improve stroke-induced inflammatory damage through direct binding HMGB1 and negative regulation of HMGB1-TLR4 downstream cytokine signaling activity.

Graphical Abstract