Department of Molecular Medicine, Ewha Womans University Medical School, Mok-6-dong 911-1, Yangchun-Ku, Seoul 158-710, Korea.
J Pharmacol Exp Ther. 2012 Apr;341(1):59-67. doi: 10.1124/jpet.111.189035. Epub 2011 Dec 29.
Microglial activation plays a pivotal role in the pathogenesis of various neurologic disorders, such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. Thus, controlling microglial activation is a promising therapeutic strategy for such brain diseases. In the present study, we found that a ginseng saponin metabolite, compound K [20-O-D-glucopyranosyl-20(S)-protopanaxadiol], inhibited the expressions of inducible nitric-oxide synthase, proinflammatory cytokines, monocyte chemotactic protein-1, matrix metalloproteinase-3, and matrix metalloproteinase-9 in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary cultured microglia. Subsequent mechanistic studies revealed that compound K suppressed microglial activation via inhibiting reactive oxygen species, mitogen-activated protein kinases, and nuclear factor-κB/activator protein-1 activities with enhancement of heme oxygenase-1/antioxidant response element signaling. To address the anti-inflammatory effects of compound K in vivo, we used two brain disease models of mice: sepsis (systemic inflammation) and cerebral ischemia. Compound K reduced the number of Iba1-positive activated microglia and inhibited the expressions of tumor necrosis factor-α and interleukin-1β in the LPS-induced sepsis brain. Furthermore, compound K reduced the infarct volume of ischemic brain induced by middle cerebral artery occlusion and suppressed microglial activation in the ischemic cortex. The results collectively suggest that compound K is a promising agent for prevention and/or treatment of cerebral ischemia and other neuroinflammatory disorders.
小胶质细胞激活在多种神经疾病的发病机制中起着关键作用，如脑缺血、阿尔茨海默病和帕金森病。因此，控制小胶质细胞激活是治疗这些脑部疾病的一种有前途的策略。在本研究中，我们发现一种人参皂苷代谢物，化合物 K [20-O-D-吡喃葡萄糖基-20(S)-原人参二醇]，可抑制脂多糖 (LPS) 刺激的 BV2 小胶质细胞和原代培养小胶质细胞中诱导型一氧化氮合酶、促炎细胞因子、单核细胞趋化蛋白-1、基质金属蛋白酶-3 和基质金属蛋白酶-9 的表达。随后的机制研究表明，化合物 K 通过抑制活性氧、丝裂原活化蛋白激酶和核因子-κB/激活蛋白-1 活性，并增强血红素加氧酶-1/抗氧化反应元件信号，抑制小胶质细胞激活。为了研究化合物 K 在体内的抗炎作用，我们使用了两种小鼠脑部疾病模型：脓毒症（全身炎症）和脑缺血。化合物 K 减少了 LPS 诱导的脓毒症大脑中 Iba1 阳性激活小胶质细胞的数量，并抑制了肿瘤坏死因子-α和白细胞介素-1β的表达。此外，化合物 K 减少了大脑中动脉闭塞引起的缺血性脑梗死体积，并抑制了缺血皮质中小胶质细胞的激活。这些结果表明，化合物 K 是预防和/或治疗脑缺血和其他神经炎症性疾病的一种有前途的药物。
