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

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.