Sevoflurane-induced cognitive decline in aged mice: Involvement of toll-like receptors 4

• Published in: Brain research bulletin 2020-12, Vol.165, p.23-29
• Main Authors: Fei, Xiang, Wang, Jin-xin, Wu, Yao, Dong, Ning, Sheng, Zhi-yong
• Format: Article
• Language: English
• Subjects: Cognitive decline; Pro-inflammatory cytokines; Sevoflurane; Toll-like receptors 4
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2020.08.030

•TLR4 deficiency protects against sevoflurane-induced cognitive decline.•TLR4 deficiency abrogates low-grade inflammation in the hippocampus.•Peripheral TNF-α administration triggers cytokine cascade in the hippocampus.•TLR4 mediates sevoflurane-induced cognitive decline in aged mice. Toll-like receptors 4 (TLR4) contributes to the pathogenesis of some neurodegenerative diseases. However, little is known about whether TLR4 is associated with sevoflurane-induced cognitive decline. This investigation aims to address the effect of global TLR4 gene knockout on cognitive decline following sevoflurane exposure to mice. Wild-type and TLR4−/− mice were exposed to 3% sevoflurane. Novel object recognition test and Y-maze test were used to analyze cognitive function. Tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in plasma and hippocampus were measured by ELISA. Peripheral administration of recombinant TNF-α to TLR4−/− mice was used to observed the role of TNF-α in cognitive function following sevoflurane. Our results showed that, in contrast to wild-type mice, TLR4 deficiency protected against the cognitive function impairment following sevoflurane exposure, and abrogated IL-1β, IL-6 and TNF-α response to sevoflurane in the system and the hippocampus. Subcutaneous administration of recombinant TNF-α elevated these cytokine levels in the hippocampus, and resulted in cognitive decline in TLR4−/− mice exposed to sevoflurane. Taken together, our results identify the crucial role of TLR4 in sevoflurane-induced cognitive decline, and showed that TLR4 mediated pro-inflammatory cytokine response to sevoflurane, and consequent cognitive decline in aged mice exposed to sevoflurane, and imply a novel target for improvement and therapy of sevoflurane-associated cognitive decline.