| 中文摘要 |
穿心蓮乙素（andrographolide）曾被報導具有抗發炎細胞（嗜中性白血球及微膠細胞）活化作用，但其對中樞神經系統的保護作用並不清楚。本研究以大鼠腦部缺血再灌流（ischemic/reperfusion，CI/R）引發腦中風（ischemic stroke）模式探討穿心蓮乙素之中樞保護作用。大鼠中風後1小時投予穿心蓮乙素（5-10 μg/kg, i.v.），並於中風後24小時評估，可以依劑量相關的方式減少腦梗塞區域 （infarction），並顯著改善大鼠之運動神經行為能力（neurologicaldeficits）；中風鼠腦部主要病理生化指標如自由基（ROS）、硝化蛋白質（nitrotyrosine）也都顯著被穿心蓮乙素抑制。中風也造成病理因子iNOS、gp91phox/NADPH oxidase 2（NOX2）及IL-1β大量表現，且與轉錄因子NF-κB及HIF-1α之大量表現平行，而這些現象都可因投予穿心蓮乙素而顯著下降；因此我們推測穿心蓮乙素可經由抑制NF-κB及HIF-1α兩轉錄因子的活化減少中風造成的大量自由基、iNOS、NOX2及IL-1β表現，達到中樞神經保護效果，因此穿心蓮乙素應有潛力發展成為治療缺血型中風的神經保護藥物。Andrographolide, an active component isolated from Andrographis paniculata, has been reported to exhibit anti-inflammatory effects in neutrophils and microglial cells, but its effects on central nervous system (CNS) are unclear. In this study, we explored the CNS protective effect of andrographolide in an ischemic stroke animal model. We performed a cerebral ischemic/reperfusion (CI/R) injury in rats to study whether treatment of andrographolide (5-10 μg/kg, i.v.) 1 h after ischemia could protect rats against stroke. Treatment with andrographolide dose-dependently ameliorated CI/R-induced brain infarction (reduced by 32%~51%) and improved neurological deficits in rats at day 1 after stroke. Elevated pathophysiological markers including reactive oxygen species (ROS) production and protein nitrosylation were significantly reduced by andrographolide. CI/R dramatically enhanced expression of inducible nitric oxide synthase (iNOS), gp91phox/NADPH oxidase 2 (NOX2) and interleukin-1β (IL-1β) that paralleled to the activation of nuclear factor-kappa B (NF-κB) and hypoxia-inducing factor 1-alpha (HIF-1α), and all were significantly diminished by andrographolide. Andrographolide compromises CI/R induced expression of iNOS and gp91phox/NOX2 through impairing NF-κB and HIF-1α activation that confers it as a potential ischemic stroke therapeutic agent. |
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