高车前素预防老年大鼠由七氟醚诱发的记忆障碍
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Hispidulin prevents sevoflurane— Induced memory dysfunction in aged rats
背景与目的：七氟醚作为一种广泛使用的全身麻醉药，发现它可以诱导老年人的认知和记忆障碍。这可能会增加患老年痴呆症AD的风险。本研究探讨了一种天然黄酮类化合物高车前素对七氟醚诱发的记忆功能障碍的神经保护作用。
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方法：利用老龄大鼠模型，对七氟醚在记忆功能上的影响进行了评价。用TUNEL分析方法对大鼠海马体中的凋亡细胞进行了评估。用WB检测海马体中的细胞凋亡相关蛋白质标记物水平。研究还检测了七氟醚和高车前素对Aβ累积的影响。此外，通过测量促炎细胞因子的表达，以及从胞浆到细胞核的Nf-kb p65的易位，评估了高车前素对七氟醚-诱发的神经炎症的衰减效应。在海马体中也发现了Nrf2的激活。此外，还用体外模型研究了高车前素对七氟醚-诱导的细胞凋亡、人类神经胶质瘤H4中Aβ累积和神经炎症的影响。为了进一步研究Nrf2在高车前素对抗七氟醚-神经毒性的神经保护活动中的作用，H4细胞转染了Nrf2靶向siRNA，这导致Nrf2的表达显著减少。
结果：新物体识别和y-迷宫测试结果表明，七氟醚对老年大鼠的记忆有明显的损害，而对大鼠高车前素预处理则明显地改善了大鼠的记忆。从机制方面来说，我们的发现表明，高车前素显著减弱了七氟醚诱导的细胞凋亡、Aβ累积和神经炎症。与在体模型研究结果一致，高车前素也能减弱七氟醚诱导的细胞凋亡，降低增加的Aβ水平，以及改善H4细胞的神经炎症。此外，我们的研究结果表明，Nrf2的激活介导了对七氟醚诱发的神经毒性的神经保护作用，证明了H4细胞敲除Nrf2显著地损害了它的保护作用。
结论：我们的研究提供了体外和在体的证据，证明高车前素可以预防七氟醚引起的神经功能障碍，高车前素有可能成为一种神经保护剂，来改善接受麻醉的老年病人的认知和记忆功能。
Huang L1, Huang K2, Ning H3
Hispidulin prevents sevoflurane— Induced memory dysfunction in aged rats
Biomed Pharmacother. 2018 Jan;97:412-422. doi: 10.1016/j.biopha.2017.10.142.
BACKGROUND: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.
METHODS: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.
RESULTS: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.
CONCLUSIONS: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.
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