Isoflurane-induced postoperative cognitive dysfunction is mediated by Hypoxia-inducible factor-1α-dependent neuroinflammation in aged rats

Abstract

Elderly patients are at high risk of developing postoperative cognitive dysfunction (POCD) after prolonged exposure to inhaled anesthetics. However, the pathogenesis of POCD remains unknown. Hypoxia-inducible factor-1α (HIF-1α) is activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1α in isoflurane-induced neuroinflammation and the resulting cognitive impairment. Following a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increased expression of HIF-1α protein, activation of nuclear factor (NF)-κB signaling and increased expression of TNF-1α were observed in the hippocampus of isoflurane-exposed rats compared with the control group. Pharmacological inhibition of HIF-1α activation by 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol (YC-1) markedly suppressed the enhanced expression of HIF-1α, disrupted NF-κB signaling pathway activity and inhibited the isoflurane-induced increase of TNF-1α expression. YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits according to the results of the Morris water maze task. These results suggest that hippocampal HIF-1α appears to be involved in an upstream mechanism of isoflurane-induced cognitive impairment. Further research is warranted to fully clarify the pathogenesis and investigate HIF-1α as a potential therapeutic target for POCD.