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Objective <p>Preserving intestinal barrier integrity and modulating post-stroke gut inflammatory milieu have garnered increasing attention as novel therapeutic strategies for cerebral ischemia–reperfusion injury (CIRI). Parthenolide (PTL) demonstrates potent anti-inflammatory properties through multiple pharmacological pathways. While accumulating preclinical evidence supports PTL's neuroprotective efficacy in CIRI and other neurological conditions, its therapeutic effects on gut–brain axis signaling pathways remain poorly characterized. This investigation was specifically undertaken to comprehensively assess PTL's therapeutic potential in mitigating CIRI-induced cognitive deficits, and mechanistically decipher its regulatory effects on gut-derived inflammatory mediators and barrier-protective mechanisms.</p> Methods <p>A rat model of middle cerebral artery occlusion followed by reperfusion (MCAO/R) was used, with PTL administered at various doses. Cognitive function was evaluated using neurological deficit scores, the novel object recognition test, and the Morris water maze. Hippocampal pathology was assessed by Nissl staining, while the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay was used to detect neuronal apoptosis in the hippocampus. Histopathological changes in the colon were examined with hematoxylin and eosin staining. Proinflammatory cytokines expression were measured by enzyme-linked immunosorbent assay. Tight junction proteins and nuclear factor kappa-B (NF-κB) pathway proteins were analyzed by immunofluorescence and Western blot. In vitro studies were conducted using the lipopolysaccharide (LPS)-induced rat intestinal epithelial cell line IEC-6.</p> Results <p>PTL significantly alleviated cognitive deficits caused by CIRI in a dose-dependent manner. Additionally, it exhibited marked protective effects against neuronal damage and neuroinflammation induced by brain I/R. Furthermore, PTL mitigated intestinal inflammation, barrier dysfunction, and systemic inflammation in MCAO/R rats. PTL effectively blocked the NF-κB axis. NF-κB overexpression counteracted the protective impact of PTL on intestinal epithelial cells injured by LPS.</p> Conclusion <p>PTL maintains intestinal homeostasis and ameliorates cognitive dysfunction following CIRI by inhibiting the NF-κB axis.</p>

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Parthenolide attenuates cognitive impairment following cerebral ischemia–reperfusion injury by inhibiting the intestinal NF-κB signaling pathway and maintaining gut homeostasis

  • 期刊论文

  • 发表日期：

    2025年5月15日

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  • Yun Zhang,
  • JiaYi Huang,
  • ShiQing Gao,
  • Ling Lin,
  • YongBing Zheng

摘要

Objective

Preserving intestinal barrier integrity and modulating post-stroke gut inflammatory milieu have garnered increasing attention as novel therapeutic strategies for cerebral ischemia–reperfusion injury (CIRI). Parthenolide (PTL) demonstrates potent anti-inflammatory properties through multiple pharmacological pathways. While accumulating preclinical evidence supports PTL's neuroprotective efficacy in CIRI and other neurological conditions, its therapeutic effects on gut–brain axis signaling pathways remain poorly characterized. This investigation was specifically undertaken to comprehensively assess PTL's therapeutic potential in mitigating CIRI-induced cognitive deficits, and mechanistically decipher its regulatory effects on gut-derived inflammatory mediators and barrier-protective mechanisms.

Methods

A rat model of middle cerebral artery occlusion followed by reperfusion (MCAO/R) was used, with PTL administered at various doses. Cognitive function was evaluated using neurological deficit scores, the novel object recognition test, and the Morris water maze. Hippocampal pathology was assessed by Nissl staining, while the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay was used to detect neuronal apoptosis in the hippocampus. Histopathological changes in the colon were examined with hematoxylin and eosin staining. Proinflammatory cytokines expression were measured by enzyme-linked immunosorbent assay. Tight junction proteins and nuclear factor kappa-B (NF-κB) pathway proteins were analyzed by immunofluorescence and Western blot. In vitro studies were conducted using the lipopolysaccharide (LPS)-induced rat intestinal epithelial cell line IEC-6.

Results

PTL significantly alleviated cognitive deficits caused by CIRI in a dose-dependent manner. Additionally, it exhibited marked protective effects against neuronal damage and neuroinflammation induced by brain I/R. Furthermore, PTL mitigated intestinal inflammation, barrier dysfunction, and systemic inflammation in MCAO/R rats. PTL effectively blocked the NF-κB axis. NF-κB overexpression counteracted the protective impact of PTL on intestinal epithelial cells injured by LPS.

Conclusion

PTL maintains intestinal homeostasis and ameliorates cognitive dysfunction following CIRI by inhibiting the NF-κB axis.