Andrographolide Inhibits PI3K/AKT-Dependent NOX2 and iNOS Expression Protecting Mice against Hypoxia/Ischemia-Induced Oxidative Brain Injury
Andrographolide Inhibits PI3K/AKT-Dependent NOX2 and iNOS Expression Protecting Mice against Hypoxia/Ischemia-Induced Oxidative Brain Injury
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DOI：
10.1055/s-0030-1271019
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发表时间：
2011-10-01
期刊：
影响因子：
2.7
通讯作者：
Shen, Yuh-Chiang
中科院分区：
文献类型：
--
作者：
Chern, Chang-Ming;Liou, Kuo-Tong;Shen, Yuh-Chiang
本研究旨在探讨穿心莲内酯对小鼠脑缺血/再灌注（CI/R）缺氧诱导的氧化/亚硝化脑损伤的保护作用机制。使用氧-葡萄糖剥夺（OGD）随后再给BV-2小胶质细胞充氧来模拟体外缺氧。我们的结果表明，用穿心莲内酯（10-100 μ g/kg，i. v.）缺氧后1h，可减轻CI/R诱导的小鼠氧化/亚硝化应激、脑梗死和神经功能缺损，并提高其存活率。CI/R诱导小鼠脑中活性氧（ROS）的显著产生和蛋白质亚硝基化的显著增加;这主要是由于NADPH氧化酶2（NOX 2）、诱导型一氧化氮合酶（iNOS）的表达增强以及由于核因子-κ B（NF-κ B）和缺氧诱导因子1-α（HIF-1 α）的活化导致的CD 11 B细胞浸润。所有这些变化均被穿心莲内酯显著减弱。在BV-2细胞中，OGD通过磷脂酰肌醇-3-激酶（PI 3 K）/AKT依赖性NF-κ B和HIF-1 α途径上调NOX 2和iNOS，诱导ROS和一氧化氮产生，这些变化被穿心莲内酯和LY 294002抑制。我们的研究结果表明，穿心莲内酯可能通过损害PI 3 K/AKT依赖的NF-κ B和HIF-1 α的激活来降低NOX 2和iNOS的表达。这损害了小胶质细胞的激活，然后反过来又介导了穿心莲在CI/R小鼠中的保护作用。
This study aimed to explore the mechanisms by which andrographolide protects against hypoxia-induced oxidative/nitrosative brain injury provoked by cerebral ischemic/reperfusion (CI/R) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone CI/R injury with andrographolide (10-100 mu g/kg, i.v.) at 1 h after hypoxia ameliorated CI/R-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. CI/R induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (NOX2), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b cells due to activation of nuclear factor-kappa B (NF-kappa B) and hypoxia-inducible factor 1-alpha (HIF-1 alpha). All these changes were significantly diminished by andrographolide. In BV-2 cells, OGD induced ROS and nitric oxide production by upregulating NOX2 and iNOS via the phosphatidylinositol-3-kinase (PI3K)/AKT-dependent NF-kappa B and HIF-1 alpha pathways, and these changes were suppressed by andrographolide and LY294002. Our results indicate that andrographolide reduces NOX2 and iNOS expression possibly by impairing PI3K/AKT-dependent NF-kappa B and HIF-1 alpha activation. This compromises microglial activation, which then, in turn, mediates andrographolide's protective effect in the CI/R mice.