QBT improved cognitive dysfunction in rats with vascular dementia by regulating the Nrf2/xCT/GPX4 and NLRP3/Caspase-1/GSDMD pathways to inhibit ferroptosis and pyroptosis of neurons.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam ; New York : Elsevier Science, c2001-
    • Subject Terms:
      NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism ; NF-E2-Related Factor 2*/metabolism ; Ferroptosis*/drug effects ; Dementia, Vascular*/drug therapy ; Dementia, Vascular*/metabolism ; Dementia, Vascular*/psychology ; Pyroptosis*/drug effects ; Neurons*/drug effects ; Neurons*/pathology ; Neurons*/metabolism ; Cognitive Dysfunction*/drug therapy ; Cognitive Dysfunction*/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism ; Caspase 1*/metabolism ; Rats, Sprague-Dawley* ; Signal Transduction*/drug effects; Animals ; Male ; Rats ; Neuroprotective Agents/therapeutic use ; Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Intracellular Signaling Peptides and Proteins/metabolism ; Humans ; Gasdermins ; Phosphate-Binding Proteins
    • Abstract:
      Background: The novel phthalein component QBT, extracted from Ligusticum chuanxiong, shows promising biological activity against cerebrovascular diseases. This study focused on ferroptosis and pyroptosis to explore the effects of QBT on nerve injury, cognitive dysfunction, and related mechanisms in a rat model of vascular dementia (VaD).
      Methods: We established a rat model of VaD and administered QBT as a treatment. Cognitive dysfunction in VaD rats was evaluated using novel object recognition and Morris water maze tests. Neuronal damage and loss in the brain tissues of VaD rats were assessed with Nissl staining and immunofluorescence. Furthermore, we investigated the neuroprotective mechanisms of QBT by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/cystine-glutamate antiporter (xCT)/glutathione peroxidase 4 (GPX4) and Nod-like receptor family pyrin domain-containing 3 (NLRP3)/cysteine-requiring aspartate protease-1 (Caspase-1)/Gasdermin D (GSDMD) pathways to inhibit ferroptosis and pyroptosis both in vivo and in vitro.
      Results: Our findings indicated that QBT significantly ameliorated neuronal damage and cognitive dysfunction in VaD rats. Additionally, QBT reversed abnormal changes associated with ferroptosis and pyroptosis in the brains of VaD rats, concurrently up-regulating the Nrf2/xCT/GPX4 pathway and down-regulating the NLRP3/Caspase-1/GSDMD pathway to inhibit ferroptosis and pyroptosis in neuronal cells, thereby exerting a neuroprotective role.
      Conclusion: In summary, QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, demonstrating a neuroprotective effect by inhibiting ferroptosis and pyroptosis in neuronal cells. This study offers a novel perspective and theoretical foundation for the future development of drugs targeting VaD.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Cognitive dysfunction; Ferroptosis; Pyroptosis; QBT; Vascular dementia
    • Accession Number:
      0 (NLR Family, Pyrin Domain-Containing 3 Protein)
      0 (NF-E2-Related Factor 2)
      0 (Nlrp3 protein, rat)
      EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
      EC 3.4.22.36 (Caspase 1)
      0 (Nfe2l2 protein, rat)
      0 (Gsdmd protein, rat)
      0 (Neuroprotective Agents)
      EC 1.11.1.9 (glutathione peroxidase 4, rat)
      0 (Intracellular Signaling Peptides and Proteins)
      0 (Gasdermins)
      0 (Phosphate-Binding Proteins)
    • Publication Date:
      Date Created: 20240912 Date Completed: 20241008 Latest Revision: 20241017
    • Publication Date:
      20241017
    • Accession Number:
      10.1016/j.intimp.2024.113070
    • Accession Number:
      39265351