异甘草素通过抗氧化和抗炎活性减轻脂多糖诱导的认知障碍

异甘草素通过抗氧化和抗炎活性减轻脂多糖诱导的认知障碍

贵州医科大学     麻醉与心脏电生理课题组

翻译：乔家康  编辑：张中伟  审核：曹莹

罂 粟 摘 要 

背景：氧化应激和神经炎症是许多神经系统疾病常见的核心致病机制。Isoliquiritigenin（ISL）是甘草中的一种黄酮类化合物，具有多种药理特性，包括抗炎活性，并已证明对急性神经损伤具有保护作用。然而，对认知障碍的潜在作用还没有得到广泛的研究。我们通过脑室内注射脂多糖（LPS）建立了大鼠认知障碍模型，并研究了ISL预处理对认知功能、海马损伤、海马各种突触蛋白的表达、抗氧化酶、促炎症细胞因子以及控制抗氧化和促炎症反应的信号因子的影响。

结果：

单独接受LPS的大鼠在Morris水迷宫试验中表现出空间学习障碍，表现为比未经处理的对照组有更长的平均逃脱潜伏期，更少的平台穿越，以及在目标象限的平均时间更短。ISL预处理扭转了这些缺陷以及LPS诱导的海马突触蛋白、突触后密度-95、脑源性神经营养因子、超氧化物歧化酶、谷胱甘肽过氧化物酶和BCL-2的表达水平下降。ISL预处理还能逆转LPS诱导的TUNEL阳性（凋亡）细胞、BAX/BCL-2比率以及肿瘤坏死因子-α、白细胞介素（IL）-1β、IL-6和C-C图案趋化因子配体3表达水平的增加。ISL预处理增加了磷酸化（p）-GSK-3β、核NRF2、HO-1 mRNA和NQO1 mRNA的表达水平，并逆转了LPS诱导的核因子（NF）-κB的核转位。

结论：ISL通过促进或维持抗氧化能力和抑制神经炎症，可能通过磷酸化依赖性的GSK-3β失活、增强NRF2反应性抗氧化基因的表达和抑制NF-κB反应性促炎症基因来保护LPS引起的认知障碍和神经元损伤。

原始文献来源：Zhu X, Liu J, Chen S, Xue J, Huang S, Wang Y, Chen O. Isoliquiritigenin attenuates lipopolysaccharide-induced cognitive impairment through antioxidant and anti-inflammatory activity. BMC Neurosci. 2019 Aug 6;20(1):41. 

英文原文

Isoliquiritigenin attenuates lipopolysaccharide-induced cognitive impairment through antioxidant and anti-inflammatory activity

Abstract

Background: Oxidative stress and neuroinflammation are central pathogenic mechanisms common to many neurological diseases. Isoliquiritigenin (ISL) is a flavonoid in licorice with multiple pharmacological properties, including anti-inflammatory activity, and has demonstrated protective efficacy against acute neural injury. However, potential actions against cognitive impairments have not been examined extensively. We established a rat model of cognitive impairment by intracerebroventricular injection of lipopolysaccharide (LPS), and examined the effects of ISL pretreatment on cognitive function, hippocampal injury, and hippocampal expression of various synaptic proteins, antioxidant enzymes, pro-inflammatory cytokines, and signaling factors controlling anti-oxidant and pro-inflammatory responses.

Results: Rats receiving LPS alone demonstrated spatial learning deficits in the Morris water maze test as evidenced by longer average escape latency, fewer platform crossings, and shorter average time in the target quadrant than untreated controls. ISL pretreatment reversed these deficits as well as LPS-induced decreases in the hippocampal expression levels of synaptophysin, postsynaptic density-95, brain-derived neurotrophic factor, superoxide dismutase, glutathione peroxidase, and BCL-2. ISL pretreatment also reversed LPS-induced increases in TUNEL-positive (apoptotic) cells, BAX/BCL-2 ratio, and expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 3. Pretreatment with ISL increased the expression levels of phosphorylated (p)-GSK-3β, nuclear NRF2, HO-1 mRNA, and NQO1 mRNA, and reversed LPS-induced nuclear translocation of nuclear factor (NF)-κB.

Conclusions: ISL protects against LPS-induced cognitive impairment and neuronal injury by promoting or maintaining antioxidant capacity and suppressing neuroinflammation, likely through phosphorylation-dependent inactivation of GSK-3β, enhanced expression of NRF2-responsive antioxidant genes, and suppression of NF-κB-responsive pro-inflammatory genes.