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

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.