Andrographolide reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation
Andrographolide reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation
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DOI：
10.1124/jpet.103.059683
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发表时间：
2004-03-01
影响因子：
3.5
通讯作者：
Hong, JS
中科院分区：
文献类型：
--
作者：
Wang, TG;Liu, B;Hong, JS
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重要作用。最近的报道表明，穿心莲（ANDRO）具有抗炎作用，通过调节巨噬细胞和中性粒细胞的活动。而小胶质细胞，巨噬细胞在大脑中的对应物，是中枢神经系统中的炎症过程中的关键，ANDRO对炎症介导的神经变性的影响还没有被检查。在这项研究中，我们表明，无论是预处理和后处理与ANDRO表现出显着的保护作用，对脂多糖（LPS）诱导的神经毒性混合神经元胶质细胞培养，确定[H-3]多巴胺的摄取和免疫细胞化学分析。相比之下，在神经元富集培养物中，ANDRO对1-甲基-4-苯基吡啶（0.5 μ M）诱导的神经毒性没有保护作用。ANDRO显著减弱LPS诱导的小胶质细胞活化和活性氧、肿瘤坏死因子-α、一氧化氮和前列腺素E-2的产生。此外，ANDRO剂量依赖性衰减LPS诱导的BV-2小胶质细胞诱导型一氧化氮合酶和环氧合酶-2蛋白的表达，通过Western blot测定。这些发现表明，ANDRO通过抑制小胶质细胞活化减少中脑神经元-胶质细胞培养物中炎症介导的多巴胺能神经变性。此外，这些结果表明，ANDRO可能具有治疗炎症相关的神经退行性疾病，如帕金森病的临床效用。
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 [H-3]dopamine uptake and immunocytochemical analysis. In contrast, ANDRO showed no protective effect on 1-methyl-4-phenyl-pyridine (0.5 muM)-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.