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灵芝提取物通过抑制小胶质细胞激活保护多巴胺能神经元

丁晖, 周明, 张瑞萍, 徐胜利^*

首都医科大学宣武医院，北京市老年病研究所神经生物学研究室，教育部神经退行性疾病重点实验室，北京 100053

摘要

近来的研究表明，神经炎症在帕金森病(Parkinson’s disease, PD)的发病过程中起着重要的作用，因此通过抑制神 经炎症而保护黑质多巴胺能神经元可能是一种具有潜力的治疗策略。本研究组前期的临床试验表明，灵芝(Ganoderma lucidum, GL)具有潜在的神经保护作用，可能通过抗炎及免疫调节机制发挥其保护作用。本研究在神经元- 小胶质细胞共培 养的模型中观察了GL 的神经保护作用，并探讨其可能的保护机制。小胶质细胞单独或与MES23.5 多巴胺能神经细胞共培 养，脂多糖(lipopolysaccharide, LPS, 0.25 μg/mL)孵育24 h 作为阳性对照，试验组分别加入GL 提取物(50~400 μg/mL)和/ 或 MPP+ 处理的MES23.5 细胞膜碎片(150 μg/mL) ；检测小胶质细胞激活情况及其产生的有害因子和MES23.5 细胞[3H]DA摄取 能力。结果显示，LPS 或MPP+ 损伤的MES23.5 膜碎片均可激活小胶质细胞。同时，GL 提取物可以显著降低小胶质细胞 源性炎症因子和细胞毒性因子(NO、TNF-α、L-1 β)的产生，并呈一定的浓度依赖性；并同样可以下调TNF-α 和L-1 βmRNA 水平的表达。此外，GL 还可明显对抗由小胶质细胞激活和MPP+ 介导的多巴胺能神经细胞[3H]DA 摄取抑制。以上结果提 示，GL 主要通过抑制小胶质细胞激活，减少其神经毒性因子的释放而保护多巴胺能神经细胞。GL 可能成为治疗PD 的潜 在药物。

关键词： 帕金森病; 小胶质细胞; 灵芝; 神经炎症; 神经保护

分类号：R329

[Ganoderma lucidum extract protects dopaminergic neurons through inhibiting the production of inflammatory mediators by activated microglia.] [Ariticle in Chinese]

DING Hui, ZHOU Ming, ZHANG Rui-Ping, XU Sheng-Li^*

Department of Neurobiology, Institute of Geriatrics of Beijing, Xuanwu Hospital of the Capital University of Medical Sciences, Key Laboratory for Neurodegenerative Disease of Ministry of Education, Beijing 100053, China

Abstract

Abundant evidence has suggested that neuroinflammation participates in the pathogenesis of Parkinson’s disease (PD). The emerging evidence has supported that microglia may play key roles in the progressive neurodegeneration in PD and might be a promising therapeutic target. Ganoderma lucidum (GL), a traditional Chinese medicinal herb, has been shown potential neuroprotective effect in our clinical trials that lead us to speculate that it might possess potent anti-inflammatory and immunomodulating properties. To test this hypothesis, the present study investigated the potential neuroprotective effect of GL and underlying mechanism through inhibiting microglial activation using co-cultures of dopaminergic neurons and microglia. The cultures of microglia or MES23.5 cells alone or together were treated for 24 h with lipopolysaccharide (LPS, 0.25 μg/mL) as a positive control, GL extracts (50-400 μg/mL) or MES23.5 cell membrane fragments (150 μg/mL) were used in treatment groups. Microglia activation, microglia-derived harmful factors and [3H]dopamine ([3H]DA) uptake of MES23.5 cells were analyzed. The results showed that microglia were activated by LPS and MPP+-treated MES23.5 cell membrane fragments, respectively. Meanwhile, GL extracts significantly prevented the production of microglia-derived proinflammatory and cytotoxic factors, including nitric oxide, tumor necrosis factor-α(TNF-α) and interleukin 1β (IL-1β), in a dose-dependent manner and down-regulated the TNF-α and IL-1β expressions on mRNA level. In addition, GL extracts antagonized the reduction of [3H]DA uptake induced by MPP+ and microglial activation. In conclusion, these results suggest that GL may be a promising agent for the treatment of PD through anti-inflammation.

Key words: Parkinson’s disease; microglia; Ganoderma; neuroinflammation; neuroprotection

收稿日期：2010-08-31　　录用日期：2010-11-17

通讯作者：徐胜利　　E-mail: xushengli@yahoo.com

引用本文：

丁晖, 周明, 张瑞萍, 徐胜利. 灵芝提取物通过抑制小胶质细胞激活保护多巴胺能神经元[J]. 生理学报 2010; 62 (6): 547-554.

DING Hui, ZHOU Ming, ZHANG Rui-Ping, XU Sheng-Li. [Ganoderma lucidum extract protects dopaminergic neurons through inhibiting the production of inflammatory mediators by activated microglia.] [Ariticle in Chinese] . Acta Physiol Sin 2010; 62 (6): 547-554 (in Chinese with English abstract).