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Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway

Acta Pharmacologica Sinica volume 45, pages 248–267 (2024)Cite this article

Abstract

There are few effective and safe neuroprotective agents for the treatment of ischemic stroke currently. Caffeic acid is a phenolic acid that widely exists in a number of plant species. Previous studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/reperfusion. In this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral ischemia. Ischemia stroke was induced on rats by permanent middle cerebral artery occlusion (pMCAO). Caffeic acid (0.4, 2, 10 mg·kg−1·d−1, i.g.) was administered to the rats for 3 consecutive days before or after the surgery. We showed that either pre-pMCAO or post-pMCAO administration of caffeic acid (2 mg·kg−1·d−1) effectively reduced the infarct volume and improved neurological outcome. The therapeutic time window could last to 2 h after pMCAO. We found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation, and enhanced antioxidant capacity in pMCAO rat brain. We further demonstrated that caffeic acid down-regulated TFR1 and ACSL4, and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation (OGD/R)-treated SK-N-SH cells in vitro. Application of ML385, an Nrf2 inhibitor, blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models, evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense system. In conclusion, caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling pathway. Caffeic acid might serve as a potential treatment to relieve brain injury after cerebral ischemia.

Caffeic acid significantly attenuated cerebral ischemic injury and resisted ferroptosis both in vivo and in vitro. The regulation of Nrf2 by caffeic acid initiated the transcription of downstream target genes, which were shown to be anti-inflammatory, antioxidative and antiferroptotic. The effects of caffeic acid on neuroinflammation and ferroptosis in cerebral ischemia were explored in a primary microglia-neuron coculture system. Caffeic acid played a role in reducing neuroinflammation and resisting ferroptosis through the Nrf2 signaling pathway, which further suggested that caffeic acid might be a potential therapeutic method for alleviating brain injury after cerebral ischemia.

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Fig. 1: Effects of caffeic acid on cerebral infarction volume, neurobehavioural scores, antioxidant enzymes and oxidative damage indices in pMCAO rats.
Fig. 2: RNA-seq analysis of genes in pMCAO rat brain tissues.
Fig. 3: Caffeic acid upregulates the Nrf2 signaling pathway after cerebral ischemia.
Fig. 4: Caffeic acid exerted neuroprotective effects via the Nrf2 signaling pathway in OGD/R-treated SK-N-SH cells.
Fig. 5: Caffeic acid inhibited ferroptosis in pMCAO rats.
Fig. 6: Caffeic acid inhibited ferroptosis in OGD/R-damaged cells.
Fig. 7: Caffeic acid reversed ferroptosis via the Nrf2 signaling pathway in vitro.
Fig. 8: Caffeic acid reversed ferroptosis via the Nrf2 signaling pathway in vivo.
Fig. 9: Caffeic acid exerted anti-inflammatory properties in pMCAO rats.
Fig. 10: Caffeic acid suppressed the LPS-induced proinflammatory response in BV2 cells via Nrf2 signaling.
Fig. 11: Caffeic acid inhibited ferroptosis via the Nrf2 signaling pathway in OGD/R primary neurons and a coculture system of microglia and neurons.

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Acknowledgements

This project was supported by grants from the National Key R&D Program of China (No. 2019YFC1708901), the National Natural Science Foundation of China (No. 82073835), and the CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-028 and 2022-I2M-2-002).

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  1. These authors contributed equally: Xin-nan Li, Nian-ying Shang

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  1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Xin-nan Li, Nian-ying Shang, Yu-ying Kang, Ning Sheng, Jia-qi Lan, Jing-shu Tang, Lei Wu, Jin-lan Zhang & Ying Peng

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Contributions

XNL: Performing the experiments, Investigation, Methodology, Validation, Formal analysis, Writing the original draft; NYS: Performing the experiments, Investigation, Methodology, Validation, Formal analysis, Writing the original draft; YYK: Performing the experiments, Methodology; NS: Performing the experiments, Methodology; JQL: Performing the experiments, Methodology; JST: Performing the experiments, Methodology; LW: Methodology, Supervision; JLZ: Conceptualization, Funding acquisition, Project administration, Supervision, Validation; YP: Conceptualization, Funding acquisition, Project administration, Supervision, Validation and Writing-review. All authors have read and approved the final manuscript. All data were generated in-house and no paper mill was used. All authors agree to be accountable for all aspects of the work, ensuring its integrity and accuracy.

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Correspondence to Jin-lan Zhang or Ying Peng.

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Li, Xn., Shang, Ny., Kang, Yy. et al. Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway. Acta Pharmacol Sin 45, 248–267 (2024). https://doi.org/10.1038/s41401-023-01177-5

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