2. Academic Validation
  3. Farrerol alleviates cognitive impairments in chronic cerebral hypoperfusion via suppressing NLRP3 inflammasome-mediated pyroptosis

Farrerol alleviates cognitive impairments in chronic cerebral hypoperfusion via suppressing NLRP3 inflammasome-mediated pyroptosis

  • Int Immunopharmacol. 2025 Apr 24:153:114442. doi: 10.1016/j.intimp.2025.114442.
Jie Zhang 1,  Yaxuan Zhang 1,  Yueqi Zhang 1,  Kaili Lu 1,  Xiaojie Zhang 1,  Xiuzhe Wang 2,  Jianliang Fu 3
Affiliations

Affiliations

  • 1 Department of Neurology, Shanghai Sixth People's Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China.
  • 2 Department of Neurology, Shanghai Sixth People's Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China. Electronic address: xiuzhewang@hotmail.com.
  • 3 Department of Neurology, Shanghai Sixth People's Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China; Department of Neurology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China. Electronic address: fujianliang@163.com.
PMID: 40112599 DOI: 10.1016/j.intimp.2025.114442
Abstract

Background: Chronic cerebral hypoperfusion (CCH) serves as a critical pathological mechanism that contributes to the development of vascular dementia (VaD). NLRP3 inflammasome activation is a pivotal factor in promoting cognitive decline in CCH. Farrerol, a dihydroflavonoid derived from Rhododendron and other Ericaceae species, possesses anti-inflammatory, antioxidant, and neuroprotective properties. However, its role in regulating Pyroptosis triggered by the NLRP3 inflammasome in CCH remains unclear.

Methods: A permanent CCH rat model was generated by occluding the bilateral common carotid arteries (BCCAO), and cellular models of sustained hypoxia were used to mimic CCH in vitro. Eight weeks post-surgery, rats received farrerol treatment. Behavioral tests were conducted after four weeks of treatment. Brain tissues were analyzed via histological staining, immunofluorescence, qRT-PCR, ELISA, and Western blot. The anti-pyroptosis effects and mechanisms of farrerol were also tested in BV2 cells and primary microglia subjected to hypoglycemia and hypoxia conditions.

Results: Farrerol markedly alleviated cognitive impairments and neural damage caused by CCH. In CCH rats, farrerol suppressed the activation of the NLRP3 inflammasome, decreased the levels of IL-1β and IL-18, and reduced Pyroptosis. The in vitro experiments also demonstrated that farrerol could reduce chronic hypoxia-induced Pyroptosis by inhibiting the NLRP3 inflammasome pathway. The cellular study further showed that the beneficial effects of farrerol in CCH are via modulating the MAPK-NF-κB pathway.

Conclusion: Farrerol mitigates CCH-induced cognitive dysfunction by inhibiting NLRP3 inflammasome-associated Pyroptosis via modulating the MAPK-NF-κB signaling cascade. These findings underscore the potential of farrerol as a therapeutic candidate for CCH.

Keywords

CCH; Farrerol; NLRP3; Pyroptosis; VaD.

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