Trauma Research Center, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
Department of Anesthesia and Analgesia, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
Brain Res Bull. 2020 Dec;165:23-29. doi: 10.1016/j.brainresbull.2020.08.030. Epub 2020 Sep 7.
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.
Toll 样受体 4（TLR4）参与了一些神经退行性疾病的发病机制。然而，TLR4 是否与七氟醚诱导的认知功能下降有关尚不清楚。本研究旨在探讨 TLR4 基因敲除对七氟醚暴露后小鼠认知功能下降的影响。野生型和 TLR4 敲除小鼠暴露于 3%七氟醚中。通过新物体识别测试和 Y 迷宫测试分析认知功能。通过 ELISA 测定血浆和海马中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）。将重组 TNF-α 外周给药于 TLR4 敲除小鼠，观察 TNF-α 在七氟醚后认知功能中的作用。结果表明，与野生型小鼠相比，TLR4 缺乏可防止七氟醚暴露后认知功能障碍，并消除了系统和海马中 IL-1β、IL-6 和 TNF-α 对七氟醚的反应。重组 TNF-α 的皮下给药可提高海马中这些细胞因子的水平，并导致 TLR4 敲除小鼠在七氟醚暴露下认知功能下降。综上所述，我们的结果确定了 TLR4 在七氟醚诱导的认知功能下降中的关键作用，并表明 TLR4 介导了七氟醚引起的促炎细胞因子反应，以及随后导致老龄小鼠暴露于七氟醚后认知功能下降，提示了一种新的改善和治疗与七氟醚相关的认知功能下降的靶点。
