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首页> 外文期刊>Translational research: the journal of laboratory and clinical medicine >Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats
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Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats

机译：穿心莲内酯刺激原代脑内皮细胞中p38促分裂原活化蛋白激酶-核因子红系-2相关因子2-血红素加氧酶1信号转导，以明确预防大鼠缺血性中风

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Stroke pathogenesis involves complex oxidative stress-related pathways. The nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) pathways have been considered molecular targets in pharmacologic intervention for ischemic diseases. Andrographolide, a labdane diterpene, has received increasing attention in recent years because of its various pharmacologic activities. We determined that andrographolide modulates the mitogen-activated protein kinase (MAPK)-Nrf2-HO-1 signaling cascade in primary cerebral endothelial cells (CECs) to provide positive protection against middle cerebral artery occlusion (MCAO)induced ischemic stroke in rats. In the present study, andrographolide (10 mu M) increased HO-1 protein and messenger RNA expressions, Nrf2 phosphorylation, and nuclear translocation in CECs, and these activities were disrupted by a p38 MAPK inhibitor, SB203580, but not by the extracellular signal-regulated kinase inhibitor PD98059 or c-Jun amino-terminal kinase inhibitor SP600125. Similar results were observed in confocal microscopy analysis. Moreover, andrographolide-induced Nrf2 and HO-1 protein expressions were significantly inhibited by Nrf2 small interfering RNA. Moreover, HO-1 knockdown attenuated the protective effect of andrographolide against oxygen-glucose deprivation-induced CEC death. Andrographolide (0.1 mg/kg) significantly suppressed free radical formation, blood-brain barrier disruption, and brain infarction in MCAO-insulted rats, and these effects were reversed by the HO-1 inhibitor zinc protoporphyrin IX. The mechanism is attributable to HO-1 activation, as directly evidenced by andrographolide-induced pronounced HO-1 expression in brain tissues, which was highly localized in the cerebral capillary. In conclusion, andrographolide increased Nrf2-HO-1 expression through p38 MAPK regulation, confirming that it provides protection against MCAO-induced brain injury. These findings provide strong evidence that andrographolide could be a therapeutic agent for treating ischemic stroke or neurodegenerative diseases.
机译：中风的发病机制涉及复杂的氧化应激相关途径。在缺血性疾病的药物干预中，核因子红系2相关因子2（Nrf2）和血红素加氧酶1（HO-1）途径被认为是分子靶标。穿心莲内酯是一种拉丹烷二萜，由于其多种药理活性，近年来受到越来越多的关注。我们确定穿心莲内酯调节原发性脑内皮细胞（CECs）中的促分裂原活化蛋白激酶（MAPK）-Nrf2-HO-1信号级联反应，以提供对大鼠中脑动脉阻塞（MCAO）引起的缺血性卒中的积极保护。在本研究中，穿心莲内酯（10μM）增加了CEC中HO-1蛋白和信使RNA的表达，Nrf2磷酸化以及核易位，并且这些活性被p38 MAPK抑制剂SB203580破坏，但不受细胞外信号干扰-调节的激酶抑制剂PD98059或c-Jun氨基末端激酶抑制剂SP600125。共聚焦显微镜分析观察到相似的结果。此外，穿心莲内酯诱导的Nrf2和HO-1蛋白表达被Nrf2小干扰RNA显着抑制。而且，HO-1敲低减弱了穿心莲内酯对氧葡萄糖剥夺引起的CEC死亡的保护作用。穿心莲内酯（0.1 mg / kg）可以显着抑制MCAO感染大鼠的自由基形成，血脑屏障破坏和脑梗塞，HO-1抑制剂锌原卟啉IX可逆转这些作用。该机制可归因于HO-1激活，这直接由穿心莲内酯诱导的脑组织中HO-1的表达明显证实，该表达高度位于脑毛细血管中。总之，穿心莲内酯通过p38 MAPK调节可增加Nrf2-HO-1的表达，从而证实它提供了抗MCAO诱导的脑损伤的保护作用。这些发现提供了强有力的证据证明穿心莲内酯可能是治疗缺血性中风或神经退行性疾病的治疗剂。

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