穿心莲内酯调节Nrg-1/ErbB4信号通路对缺血性脑卒中大鼠神经元凋亡的影响-中国药房

穿心莲内酯调节Nrg-1/ErbB4信号通路对缺血性脑卒中大鼠神经元凋亡的影响

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篇名：	穿心莲内酯调节Nrg-1/ErbB4信号通路对缺血性脑卒中大鼠神经元凋亡的影响
TITLE：	Effect of andrographolide on neuronal apoptosis in ischemic stroke rats by regulating Nrg-1/ErbB4 signaling pathway
摘要：	目的探讨穿心莲内酯（Andro）调节神经调节蛋白1（Nrg-1）/表皮生长因子受体4（ErbB4）信号通路对缺血性脑卒中（IS）大鼠神经元凋亡的影响。方法采用线栓法建立IS大鼠模型。将60只造模成功的大鼠随机分为模型组（Model组，生理盐水）、Andro低剂量组（Andro-L组，50mg/kg）、Andro高剂量组（Andro-H组，100mg/kg）和Andro-H+Dacomitinib组（100mg/kgAndro+7.5mg/kgNrg-1/ErbB4信号通路抑制剂Dacomitinib），每组15只；另取15只大鼠为Sham组（生理盐水）。灌胃给药/生理盐水，每天1次，连续7d。给药结束后，评估大鼠神经功能；检测大鼠血清中乳酸脱氢酶（LDH）、肿瘤坏死因子α（TNF-α）、白细胞介素1β（IL-1β）、IL-10、神经生长因子（NGF）水平；测定大鼠脑梗死面积；观察大鼠海马组织病理变化；检测大鼠海马神经元凋亡率和海马组织中丙二醛（MDA）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）水平及基质金属蛋白酶9（MMP-9）、剪切型胱天蛋白酶3（cleaved-caspase-3）、Nrg-1蛋白表达水平和磷酸化ErbB4（p-ErbB4）/ErbB4比值。结果与Model组比较，Andro-L组、Andro-H组大鼠Zea-Longa评分，逃避潜伏期，血清中LDH、TNF-α、IL-1β水平，脑梗死面积百分比，海马神经元凋亡率，海马组织中MDA水平和MMP-9、cleaved-caspase-3蛋白表达水平均显著降低/缩短（P＜0.05）；滞留时间、穿越平台次数，血清中IL-10、NGF水平，海马组织中CAT、SOD水平和Nrg-1蛋白表达水平、p-ErbB4/ErbB4比值均显著延长/增加/升高（P＜0.05）；海马神经组织结构损伤程度明显降低。Dacomitinib可减弱高剂量Andro对IS大鼠神经元损伤的改善作用（P＜0.05）。结论Andro可减轻IS大鼠炎症反应、氧化应激和海马组织损伤，改善神经功能；其作用机制可能与激活Nrg-1/ErbB4信号通路有关。
ABSTRACT：	OBJECTIVE To investigate the effect of andrographolide （Andro） on the neuronal apoptosis in ischemic stroke （IS） rats by regulating the neuregulin-1 （Nrg-1）/epithelial growth factor receptor 4 （ErbB4） signaling pathway. METHODS The IS rat model was established using the suture method. Sixty successfully modeled rats were randomly divided into model group （physiological saline）， Andro low-dose group （Andro-L group， 50 mg/kg）， Andro high-dose group （Andro-H group， 100 mg/kg）， and Andro-H+Dacomitinib group （100 mg/kg of Andro+7.5 mg/kg of Nrg-1/ErbB4 signaling pathway inhibitor Dacomitinib）， with 15 rats in each group. Another 15 rats were chosen as the sham group （physiological saline）. The rats were intragastrically administered medication/physiological saline once a day for 7 consecutive days. After medication， the neurological function of the rats was assessed； the levels of lactate dehydrogenase （LDH）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， IL-10， and nerve growth factor （NGF） in the rat serum were detected； the infarct area of the rat brain was measured， and the pathological changes in the hippocampal tissue of the rats were observed. Moreover， the apoptosis rate of hippocampal neurons and the levels of malondialdehyde （MDA）， superoxide dismutase （SOD）， catalase （CAT）， matrix metalloproteinase-9 （MMP-9）， cleaved-caspase- 3， Nrg-1 protein expressions and phosphorylated ErbB4 （p-ErbB4）/ErbB4 ratio in the hippocampal tissue were detected. RESULTS Compared with the model group， the Zea-Longa score， the escape latency， the serum LDH， TNF-α， IL-1β levels， the percentage of cerebral infarction area， the hippocampal neuron apoptosis rate， the MDA level and MMP-9， cleaved-caspase-3 protein expression levels in the hippocampal tissue in the Andro-L and Andro-H groups were significantly reduced/shortened （P＜0.05）. The dwelling time， the number of platform crossings， the serum IL-10， NGF levels， the CAT， SOD levels， the Nrg-1 protein expression level and p-ErbB4/ErbB4 ratio in the hippocampal tissue were significantly extended/increased （P＜0.05）； the degree of hippocampal neural tissue damage was significantly E-mail：lrxxl3@163.com reduced. Dacomitinib could significantly weaken the improvement effect of high-dose Andro on neuronal injury in IS rats （P＜0.05）. CONCLUSIONS Andro can reduce the inflammatory response， oxidative stress， and hippocampal tissue damage in IS rats， and promote neurological function. Its mechanism of action may be related to the activation of Nrg-1/ErbB4 signaling pathway.
期刊：	2024年第35卷第21期
作者：	邓敏；禹红；周祥；孙海东
AUTHORS：	DENG Min，YU Hong，ZHOU Xiang，SUN Haidong
关键字：	穿心莲内酯；缺血性脑卒中；Nrg-1/ErbB4信号通路；神经元凋亡；神经功能
KEYWORDS：	andrographolide； ischemic stroke； Nrg-1/ErbB4 signaling pathway； neuronal apoptosis； neurological function
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