Inhibition of piezo1 prevents chronic cerebral hypoperfusion-induced cognitive impairment and blood brain barrier disruption

Chronic cerebral hypoperfusion (CCH) plays a critical role in the onset and progression of vascular dementia (VD), which is now recognized as the second most common form of dementia after Alzheimer's disease (AD). The mechanosensitive piezo1 channel has been identified to play important roles in several neurological disorders. However, the roles and possible mechanisms of piezo1 in CCH-induced cognitive decline and blood brain barrier (BBB) disruption, as well as the underlying mechanisms remain elusive. In this study, the CCH model was established by bilateral common carotid artery occlusion in rats and by oxygen and glucose deprivation/reoxygenation (OGD/R) in bEnd.3 cells. The results demonstrated that the antagonist of piezo1 GsMTx4 ameliorated CCH-induced cognitive dysfunction and mitigated cerebral edema. Furthermore, this study indicated that GsMTx4 improved the permeability and integrity of BBB and protected cerebral microvasculature after CCH. In vitro, GsMTx4 improved cell viability, promoted the ability of cell motility and migration, and inhibited the degradation of BBB integrity-related proteins by inhibiting NLRP3 inflammasome activation. In addition, NLRP3 agonist abolished the beneficial effects of GsMTx4. Collectively, our results demonstrate that piezo1 might be involved in CCH-induced cognitive impairment and BBB damage, which may be at least partially mediated through regulation of NLRP3 inflammasome.