1. Academic Validation
  2. Salvianolic acid A inhibits ferroptosis and protects against intracerebral hemorrhage

Salvianolic acid A inhibits ferroptosis and protects against intracerebral hemorrhage

  • Sci Rep. 2024 May 30;14(1):12427. doi: 10.1038/s41598-024-63277-4.
Yunpeng Shi 1 Dongdong Yan 1 Chengrui Nan 1 Zhimin Sun 2 Yayu Zhuo 1 Haoran Huo 1 Qianxu Jin 3 Hongshan Yan 3 Zongmao Zhao 4 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
  • 2 Department of Neurosurgery, Third Hospital of Shijiazhuang, Shijiazhuang, 050000, Hebei, China.
  • 3 Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
  • 4 Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. zzm692017@sina.com.
  • 5 Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. zzm692017@sina.com.
Abstract

Intracerebral hemorrhage (ICH) is a common cerebral vascular disease with high incidence, disability, and mortality. Ferroptosis is a regulated type of iron-dependent, non-apoptotic programmed cell death. There is increasing evidence that Ferroptosis may lead to neuronal damage mediated by hemorrhagic stroke mediated neuronal damage. Salvianolic acid A (SAA) is a natural bioactive polyphenol compound extracted from salvia miltiorrhiza, which has anti-inflammatory, antioxidant, and antifibrosis activities. SAA is reported to be an iron chelator that inhibits lipid peroxidation and provides neuroprotective effects. However, whether SAA improves neuronal Ferroptosis mediated by hemorrhagic stroke remains unclear. The study aims to evaluate the therapeutic effect of SAA on Ferroptosis mediated by Intracerebral hemorrhage and explore its potential mechanisms. We constructed in vivo and in vitro models of intracerebral hemorrhage in rats. Multiple methods were used to analyze the inhibitory effect of SAA on Ferroptosis in both in vivo and in vitro models of intracerebral hemorrhage in rats. Then, network pharmacology is used to identify potential targets and mechanisms for SAA treatment of ICH. The SAA target ICH network combines SAA and ICH targets with protein-protein interactions (PPIs). Find the specific mechanism of SAA acting on Ferroptosis through molecular docking and functional enrichment analysis. In rats, SAA (10 mg/kg in vivo and 50 μM in vitro, p < 0.05) alleviated dyskinesia and brain injury in the ICH model by inhibiting Ferroptosis (p < 0.05). The molecular docking results and functional enrichment analyses suggested that Akt (V-akt murine thymoma viral oncogene homolog) could mediate the effect of SAA. NRF2 (Nuclear factor erythroid 2-related factor 2) was a potential target of SAA. Our further experiments showed that salvianolic acid A enhanced the Akt /GSK-3β/Nrf2 signaling pathway activation in vivo and in vitro. At the same time, SAA significantly expanded the expression of GPX4, XCT proteins, and the nuclear expression of Nrf2, while the Akt Inhibitor SH-6 and the Nrf2 inhibitor ML385 could reduce them to some extent. Therefore, SAA effectively ameliorated ICH-mediated neuronal Ferroptosis. Meanwhile, one of the critical mechanisms of SAA inhibiting Ferroptosis was activating the Akt/GSK-3β/Nrf2 signaling pathway.

Keywords

Akt/GSK-3β; Ferroptosis; Intracerebral hemorrhage; Molecular docking; NRF2; Network pharmacology; Primary cortical neurons; Salvianolic acid A.

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