HMGB1/RAGE signaling mediates the activation of microglia and participates in depressive-like behaviors and cognitive deficits in rats after ischemia-reperfusion

  • Behav Brain Res. 2025 Aug 24:492:115662. doi: 10.1016/j.bbr.2025.115662.
Lifei Fan  1 ,  Xinyue Zhang  2 ,  Xiaojia Song  2 ,  Lina Yang  3 ,  Huanhuan Liu  2 ,  Yunfei Zhang  1 ,  Kun Li  1 ,  Xuejiao Jin  2 ,  Hao Lei  2 ,  Zhaohui Zhang  4 ,  Fuping Zhang  5 ,  Jinggui Song  6
Affiliations
  • 1. The First Affiliated Hospital of Xinxiang Medical College, Xinxiang 453000, China; Henan Provincial Key Laboratory of Biological Psychiatry (Xinxiang Medical College), Xinxiang 453000, China.
  • 2. The Second Affiliated Hospital of Xinxiang Medical College, Henan Provincial Psychiatric Hospital, Xinxiang 453000, China; Henan Provincial Key Laboratory of Biological Psychiatry (Xinxiang Medical College), Xinxiang 453000, China.
  • 3. The Second Affiliated Hospital of Xinxiang Medical College, Henan Provincial Psychiatric Hospital, Xinxiang 453000, China.
  • 4. The First Affiliated Hospital of Xinxiang Medical College, Xinxiang 453000, China.
  • 5. The Second Affiliated Hospital of Xinxiang Medical College, Henan Provincial Psychiatric Hospital, Xinxiang 453000, China; Henan Provincial Key Laboratory of Biological Psychiatry (Xinxiang Medical College), Xinxiang 453000, China. Electronic address: [email protected].
  • 6. The Second Affiliated Hospital of Xinxiang Medical College, Henan Provincial Psychiatric Hospital, Xinxiang 453000, China; Henan Provincial Key Laboratory of Biological Psychiatry (Xinxiang Medical College), Xinxiang 453000, China. Electronic address: [email protected].
PMID: 40419119 DOI: 10.1016/j.bbr.2025.115662
Abstract

Post-stroke depression (PSD) is a common psychiatric complication that occurs after stroke, especially in ischemic stroke (I/S). It has been reported that high-mobility group box-1 (HMGB1) is highly expressed in clinical PSD patients, but the exact molecular mechanism of its involvement in PSD is not completely clear, the neuroinflammation may participate in its development. Thus, we established a PSD rat model, observed behavioral and cognitive deficits, and found that the HMGB1/ receptor for advanced glycation end products (RAGE) pathway were activated in microglia. Glycyrrhizin acid (GA), an inhibitor of HMGB1, inhibited microglial activation, reversed the expression of HMGB1/RAGE, and ameliorated depressive-like behaviors in PSD rats. GA also reduced the expression of MAPK and NF-κB, which further led to decreased expression of IL-1β and NLRP3 inflammasome. These results suggested that the HMGB1/RAGE pathway was involved in microglial activation in the PSD model, promoting neuroinflammation and depressive-like behaviors.

Keywords
GA; HMGB1; Microglia; Neuroinflammation; PSD; RAGE.
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