Ji'nan Central Hospital Affiliated to Shandong University, Jinan, China.
The Fourth People's Hospital of Ji'nan, Jinan, China.
Biomed Pharmacother. 2018 Jan;97:412-422. doi: 10.1016/j.biopha.2017.10.142. Epub 2017 Nov 6.
As a widely used general anesthetic, sevoflurane has been found to induce cognitive and memory defectsin the elderly. This may increase the risk of Alzheimer's disease. This study explores the neuroprotective effect of hispidulin, a natural flavone compound, against sevoflurane-induced memory dysfunction.
The effect of sevoflurane exposure on memory function was evaluated by novel object recognition and Y-maze testing using an aged rat model. The apoptotic cell death in the hippocampus of rats was assessed using a TUNEL assay. The levels of protein markers for cell apoptosis in the hippocampus were examined by western blot. The effect of sevoflurane and hispidulin on the accumulation of Aβ was also examined. In addition, the attenuating effect of hispidulin on sevoflurane-induced neuroinflammation was assessed by measuring the expression of pro-inflammatory cytokines and the translocation of NF-κB p65 from cytosol to nucleus. The activation of Nrf2 in the hippocampus was also detected. Moreover, the effect of hispidulin on sevoflurane-induced apoptosis, Aβ accumulation, and neuroinflammation was also examined in human neuroglioma H4 cells, which served as an in vitro model.To further examine the role of Nrf2 in the neuroprotective activity of hispidulin against sevoflurane-neurotoxicity, H4 cells were transfected with Nrf2 targeting siRNA, which led to a significant reduction in Nrf2 expression.
Both novel object recognition and Y-maze testing showed that sevoflurane significantly impaired the memory of aged rats, which was significantly reversed by pretreatment with hispidulin. Mechanistically, our findings revealed that hispidulin significantly attenuated sevoflurane-induced apoptotic cell death, Aβ accumulation, and neuroinflammation. In agreement with in vivo studies, hispidulin was also able to attenuate sevoflurane-induced apoptosis, increases of Aβ levels, and neuroinflammation in H4 cells. Moreover, our results showed that Nrf2 activation mediated the neuroprotective effect of hispidulin against sevoflurane-induced neurotoxicity by demonstrating that knockdown of Nrf2 in H4 cells significantly compromised its protective effects.
As our study provides in vitro and in vivo evidence that hispidulin can offer protection against sevoflurane-induced neurological dysfunction, hispidulin has the potential to be a neuroprotective agent that can improve the cognitive and memory function of elderly patients undergoing anesthesia.
七氟醚作为一种广泛应用的全身麻醉剂，已被发现可导致老年人认知和记忆功能缺陷，从而增加阿尔茨海默病的风险。本研究旨在探讨天然黄酮类化合物芹菜素对七氟醚诱导的记忆功能障碍的神经保护作用。
采用老年大鼠模型，通过新物体识别和 Y 迷宫试验评估七氟醚暴露对记忆功能的影响。采用 TUNEL 法检测大鼠海马区细胞凋亡情况。采用 Western blot 检测海马区细胞凋亡蛋白标志物的水平。通过测定 Aβ的积累，评估七氟醚和芹菜素的作用。此外，还通过测量促炎细胞因子的表达和 NF-κB p65 从细胞质向细胞核的转位，评估芹菜素对七氟醚诱导的神经炎症的抑制作用。还检测了海马区 Nrf2 的激活情况。此外，还在人神经胶质瘤 H4 细胞中检测了芹菜素对七氟醚诱导的凋亡、Aβ积累和神经炎症的抑制作用，该细胞系作为体外模型。为了进一步研究 Nrf2 在芹菜素对七氟醚神经毒性的神经保护作用中的作用，我们用 Nrf2 靶向 siRNA 转染 H4 细胞，导致 Nrf2 表达显著降低。
新物体识别和 Y 迷宫试验均显示，七氟醚显著损害老年大鼠的记忆功能，而芹菜素预处理可显著逆转这一作用。机制研究表明，芹菜素可显著减轻七氟醚诱导的细胞凋亡、Aβ积累和神经炎症。与体内研究一致，芹菜素还能减轻 H4 细胞中七氟醚诱导的凋亡、Aβ水平升高和神经炎症。此外，我们的结果表明，Nrf2 的激活介导了芹菜素对七氟醚诱导的神经毒性的神经保护作用，因为在 H4 细胞中敲低 Nrf2 显著削弱了其保护作用。
本研究提供了体内外证据，表明芹菜素可以防止七氟醚引起的神经功能障碍，因此，芹菜素有可能成为一种神经保护剂，改善接受麻醉的老年患者的认知和记忆功能。
