DCA can improve the ACI-induced neurological impairment through negative regulation of Nrf2 signaling pathway
DCA can improve the ACI-induced neurological impairment through negative regulation of Nrf2 signaling pathway
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DOI：
10.26355/eurrev_201901_16782
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Sun, Y-J
中科院分区：
文献类型：
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作者：
Bian, K-Y;Jin, H-F;Sun, Y-J
目的：探讨牛磺熊去氧胆酸（TUDCA）对急性脑梗死（ACI）所致神经功能损害的影响及其相关作用机制。 患者与方法：雄性SD大鼠60只，随机分为Sham组（n = 20）、ACI组（n = 20）和TUDCA组（n = 20）。建立大鼠大脑中动脉ACI模型。 TUDCA组大鼠静脉注射TUDCA，其余两组大鼠静脉注射等量碳酸氢钠溶液。造模后抽血检测血清谷氨酸(Glu)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)的含量。光学显微镜下观察各实验组脑梗死程度，并测量梗死面积并进行比较。采用酶联免疫吸附法（ELISA）检测血清肿瘤坏死因子-α（TNF-α）、白细胞介素-8（IL-8）、高敏C反应蛋白（hs-CRP）的含量；分别采用逆转录聚合酶链反应（RT-PCR）和Western blotting检测它们的mRNA和蛋白表达，然后进行统计分析。检测血清丙二醛（MDA）、氧化低密度脂蛋白（ox-LDL）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPX）的表达水平并进行统计分析。采用Western blotting检测核因子（红细胞源性2）样2（Nrf2）、极低密度脂蛋白受体（VLDLR）、核因子κB（NF-κB）、B细胞淋巴瘤2相关X蛋白（Bax）、caspase-3的蛋白表达，并测定灰度值，并进行统计分析。结果：TUDCA可改善ACI患者的神经功能缺损症状，降低美国国立卫生研究院卒中量表（NIHSS）评分，但提高患者日常生活能力（ADL）评分，并显着降低血清TG含量。 TC 和 LDL-C，显示出统计学显着差异 (p < 0.05)。 TUDCA显着降低ACI大鼠血清Glu含量，缩小脑梗死面积，降低血清TG。 TC 和 LDL-C 含量显示出统计学显着性差异 (p < 0.05)。此外，TUDCA还抑制TNE-α、IL-8和hs-CRP的mRNA和蛋白表达，减轻炎症反应。 TUDCA抑制MDA和ox-LDL表达，但增加SOD和GPX表达，减轻氧化应激损伤。此外,TUDCA还可负向调节Nrf2信号通路,下调VLDLR、NE-kappa B蛋白表达以及凋亡蛋白(Bax和caspase-3)的表达。结论:TUDCA可通过减轻脂质过氧化和炎症反应、减少细胞凋亡来减轻ACI所致大鼠神经功能损伤,其相关机制可能是TUDCA负向调节Nrf2信号通路。
OBJECTIVE: To investigate the effect of tauroursodeoxycholic acid (TUDCA) on neurological impairment induced by acute cerebral infarction (ACI) and its relevant mechanism of action.PATIENTS AND METHODS: A total of 60 male Sprague-Dawley (SD) rats were randomly divided into Sham group (n = 20), ACI group (n = 20), and TUDCA group (n = 20). The rat model of ACI in middle cerebral artery was established. TUDCA was intravenously injected into rats in the TUDCA group, while an equal amount of sodium bicarbonate solution was intravenously injected into the other two groups. The blood was drawn after modeling to detect the content of serum glutamate (Glu), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). The degree of cerebral infarction in each experimental group was observed under an optical microscope, and the infarct area was measured and compared. The content of serum tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and high-sensitivity C-reactive protein (hs-CRP) was detected via enzyme-linked immunosorbent assay (ELISA); mRNA and protein expressions of them were detected using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively, followed by statistical analysis. Moreover, the expression levels of serum malondialdehyde (MDA), oxidized-LDL (ox-LDL), superoxide dismutase (SOD), and glutathione peroxidase (GPX) were detected, followed by statistical analysis. The protein expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), very low-density lipoprotein receptor (VLDLR), nuclear factor-kappa B (NF-kappa B), B-cell lymphoma 2-associated X protein (Bax), and caspase-3 were detected via Western blotting, and the gray value was determined, followed by statistical analysis.RESULTS: TUDCA could improve the symptoms of neurological impairment in ACI patients, decrease the National Institute of Health Stroke Scale (NIHSS) score but increase the activity of daily living (ADL) score of patients, and significantly reduce the content of serum TG. TC, and LDL-C, showing statistically significant differences (p < 0.05). TUDCA significantly decreased the serum Glu content in ACI rats, reduced the cerebral infarction area and lowered the serum TG. TC, and LDL-C content, displaying statistically significant differences (p < 0.05). Besides, TUDCA inhibited mRNA and protein expressions of TNE-alpha, IL-8, and hs-CRP, and alleviated the inflammatory response. TUDCA inhibited MDA and ox-LDL expressions, but increased SOD and GPX expressions, and relieved oxidative stress injury. In addition, TUDCA could negatively regulate Nrf2 signaling pathway, and down-regulated VLDLR and NE-kappa B protein expressions and expressions of apoptotic proteins (Bax and caspase-3).CONCLUSIONS: TUDCA can alleviate the ACI-induced neurological impairment in rats through mitigating lipid peroxidation and inflammatory response and reducing apoptosis, whose relevant mechanism may be that TUDCA negatively regulates Nrf2 signaling pathway.