Wang Tongguang, Liu Bin, Zhang Wei, Wilson Belinda, Hong Jau-Shyong
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
J Pharmacol Exp Ther. 2004 Mar;308(3):975-83. doi: 10.1124/jpet.103.059683. Epub 2004 Jan 8.
Inflammation plays an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease. Recent reports have indicated that andrographolide (ANDRO) has an anti-inflammatory effect by modulating macrophage and neutrophil activity. Whereas microglia, the counterpart of macrophages in the brain, are pivotal in the inflammatory process in the central nervous system, the effect of ANDRO on inflammation-mediated neurodegeneration has not been examined. In this study, we show that both pretreatment and post-treatment with ANDRO exhibited a significant protective effect against lipopolysaccharide (LPS)-induced neurotoxicity in mixed neuron-glia cultures, as determined by [(3)H]dopamine uptake and immunocytochemical analysis. In contrast, ANDRO showed no protective effect on 1-methyl-4-phenyl-pyridine (0.5 microM)-induced neurotoxicity in neuron-enriched cultures. ANDRO significantly attenuated LPS-induced microglial activation and production of reactive oxygen species, tumor necrosis factor-alpha, nitric oxide, and prostaglandin E(2). Furthermore, ANDRO dose-dependently attenuated LPS-induced inducible nitric-oxide synthase and cyclooxygenase-2 protein expression in BV-2 microglia, as determined by Western blot. These findings demonstrate that ANDRO reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation. In addition, these results indicate that ANDRO may have clinical utility for the treatment of inflammation-related neurodegenerative disorders such as Parkinson's disease.
炎症在包括帕金森病在内的几种神经退行性疾病的发病机制中起着重要作用。最近的报告表明，穿心莲内酯（ANDRO）通过调节巨噬细胞和中性粒细胞活性具有抗炎作用。虽然小胶质细胞是大脑中巨噬细胞的对应物，在中枢神经系统的炎症过程中起关键作用，但ANDRO对炎症介导的神经退行性变的影响尚未得到研究。在本研究中，我们发现，通过[³H]多巴胺摄取和免疫细胞化学分析确定，ANDRO预处理和后处理均对脂多糖（LPS）诱导的混合神经元-胶质细胞培养物中的神经毒性具有显著的保护作用。相比之下，ANDRO对富含神经元的培养物中1-甲基-4-苯基吡啶（0.5微摩尔）诱导的神经毒性没有保护作用。ANDRO显著减弱了LPS诱导的小胶质细胞活化以及活性氧、肿瘤坏死因子-α、一氧化氮和前列腺素E₂的产生。此外，通过蛋白质印迹法确定，ANDRO剂量依赖性地减弱了LPS诱导的BV-2小胶质细胞中诱导型一氧化氮合酶和环氧化酶-2蛋白的表达。这些发现表明，ANDRO通过抑制小胶质细胞活化减少了中脑神经元-胶质细胞培养物中炎症介导的多巴胺能神经退行性变。此外，这些结果表明，ANDRO可能对治疗帕金森病等与炎症相关的神经退行性疾病具有临床应用价值。
