2. Academic Validation
  3. Silibinin ameliorates STING-mediated neuroinflammation via downregulation of ferroptotic damage in a sporadic Alzheimer's disease model

Silibinin ameliorates STING-mediated neuroinflammation via downregulation of ferroptotic damage in a sporadic Alzheimer's disease model

  • Arch Biochem Biophys. 2023 Jul 18;744:109691. doi: 10.1016/j.abb.2023.109691.
Panwen Liu 1,  Wenhui Chen 1,  Yu Kang 1,  Chenkang Wang 1,  Xiaoling Wang 1,  Weiwei Liu 1,  Toshihiko Hayashi 2,  Zhiyue Qiu 1,  Kazunori Mizuno 3,  Shunji Hattori 3,  Hitomi Fujisaki 3,  Takashi Ikejima 4
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
  • 2 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China; Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan.
  • 3 Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan.
  • 4 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China; Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China. Electronic address: [email protected].
PMID: 37473980 DOI: 10.1016/j.abb.2023.109691
Abstract

Ferroptosis, an iron-dependent cell death, is caused by lipid peroxidation. Noteworthily, accumulation of iron and lipid peroxidation are found in the proximity of the neuritic plaque, a hallmark of Alzheimer's disease (AD), but the relationship between Ferroptosis and neuroinflammation in AD is unclear. Silibinin, extracted from the Silybum marianum, is possibly developed as an agent for AD treatment from its neuroprotective effect, but the effect of silibinin on sporadic AD that accounts for more than 95% of AD remains unclear. To determine whether silibinin alleviates the pathogenesis of sporadic AD and investigate the underlying mechanisms, STZ-treated HT22 murine hippocampal neurons and intracerebroventricular injection of streptozotocin (ICV-STZ) rats, a sporadic AD model, were used in this study. Results show that silibinin not only promotes survival of STZ-treated HT22 cells, but also ameliorates the cognitive impairment and anxiety/depression-like behavior of ICV-STZ rats. We here demonstrate that silibinin evidently inhibits the protein level of p53 as well as upregulates the protein level of cystine/glutamate antiporter SLC7A11 and Ferroptosis inhibitor GPX4, but not p21, leading to the protection against STZ-induced ferroptotic damage. Immunofluorescent staining also shows that accumulation of lipid peroxidation induced by ferroptotic damage leads to increased fluorescence of 8-oxo-deoxyguanosine (8-OHDG), a maker of oxidized DNA. The oxidized DNA then leaks to the cytoplasm and upregulates the expression of the stimulator of interferon gene (STING), which triggers the production of IFN-β and other inflammatory cascades including NF-κB/TNFα and NLRP3/Caspase 1/IL-1β. However, the treatment with silibinin blocks the above pathological changes. Moreover, in HT22 cells with/without STZ treatment, GPX4-knockdown increases the protein level of STING, indicating that the ferroptotic damage leads to the activation of STING signaling pathway. These results imply that silibinin exerts neuroprotective effect on an STZ-induced sporadic AD model by downregulating ferroptotic damage and thus the downstream STING-mediated neuroinflammation.

Keywords

Alzheimer's disease; Ferroptosis; Neuroinflammation; STING; Silibinin.

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