The role of the Wnt/β‐catenin‐Annexin A1 pathway in the process of sevoflurane‐induced cognitive dysfunction

Postoperative cognitive decline (POCD) is a common geriatric complication, and sevoflurane is a widely accepted inducer of POCD. Although the aetiology of POCD is not clear, a breach in the blood-brain barrier (BBB) is involved in early POCD. Annexin A1 has shown protective effects on BBB function. The objective of this study was to investigate both the effects of sevoflurane on the components of the BBB and the underlying mechanism. In vivo treatment with 3.6% sevoflurane for 6 h disrupted BBB components led to fibrinogen invasion and down-regulation of Annexin A1 expression at 24 h after inhalation. The administration of human recombinant Annexin A1 (hr Annexin A1) attenuated the disruption of BBB components, thereby reducing fibrinogen invasion. In addition, the administration of hr Annexin A1 improved cognitive function after the inhalation of 3.6% sevoflurane for 6 h. Moreover, in cultured endothelial cells, 3.6% sevoflurane for 6 h increased GSK-3β and decreased β-catenin levels at 24 h after inhalation. The activation/inhibition of the Wnt/β-catenin signalling pathway attenuated/worsened the sevoflurane-induced decrease in Annexin A1. Our findings indicate that in endothelial cells, treatment with 3.6% sevoflurane for 6 h inhibits the Wnt/β-catenin signalling pathway, thereby increasing GSK-3β and decreasing β-catenin. By inhibiting this pathway, the gas anaesthetic sevoflurane down-regulated Annexin A1, which consequently breached the BBB and induced POCD. We propose the following cascade for sevoflurane-induced cognitive dysfunction: in microvascular endothelial cells, treatment with 3.6% sevoflurane for 6 h inhibits the Wnt/β-catenin signalling pathway, increasing GSK-3β and decreasing β-catenin, which down-regulates the expression of Annexin A1. This cascade leads to a breach in the blood-brain barrier, a process which is involved in the occurrence of early postoperative cognitive decline. Cover Image for this issue: doi: 10.1111/jnc.13314.