title: The role of the Wnt/β-catenin-Annexin A1 pathway in the process of sevoflurane-induced cognitive dysfunction.
abstract: 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.
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors: Nan
authors: N
authors: Hu
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors: Chao
authors: C
authors: Wang
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors: Yuxin
authors: Y
authors: Zheng
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors: Jiying
authors: J
authors: Ao
authors: Department of orthopedics, Tianjin Medical University General Hospital, Tianjin, China.
authors: Chao
authors: C
authors: Zhang
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors: Keliang
authors: K
authors: Xie
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors: Yize
authors: Y
authors: Li
authors: Department of Anesthesiology, Tianjin the Third Central Hospital, Tianjin, China.
authors: Haiyun
authors: H
authors: Wang
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors: Yonghao
authors: Y
authors: Yu
authors: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.|Department of Critical Care Medicine of Tianjin Medical University General Hospital, Tianjin, China.
authors: Guolin
authors: G
authors: Wang
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism / Q000627:therapeutic use; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008738:Methyl Ethers / Q000633:toxicity*; D055806:Microvessels / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D017305:Annexin A1; D008738:Methyl Ethers; D010975:Platelet Aggregation Inhibitors; D051176:beta Catenin; D000077149:Sevoflurane
keywords: Wnt/β-catenin; annexin A1; blood-brain barrier; postoperative cognitive decline; sevoflurane