Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action
Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action
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DOI：
10.1111/j.1460-9568.2007.05636.x
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发表时间：
2007-07-01
影响因子：
3.4
通讯作者：
Jin, Byung Kwan
中科院分区：
文献类型：
--
作者：
Park, Hyun Jung;Lee, Phil Hyu;Jin, Byung Kwan
流行病学研究报告说，吸烟与帕金森氏病(PD)的发病率较低有关，这导致了吸烟，特别是尼古丁可能具有神经保护作用的理论。最近的研究表明，胆碱能抗炎途径通过α7烟碱受体调节小胶质细胞的激活。在本研究中，我们利用脂多糖(LPS)诱导的体外和体内炎症模型，探讨尼古丁是否通过抗炎机制对多巴胺能系统具有保护作用。尼古丁预处理可显著降低小胶质细胞的活化程度，显著降低内毒素刺激诱导的肿瘤坏死因子-α的表达和释放。在小胶质细胞和中脑神经元的共同培养中，尼古丁预处理显著减少酪氨酸羟基酶免疫阳性(TH-IP)细胞的丢失，大约是单纯内毒素处理的两倍。α-银环蛇毒素是一种α-7烟碱型乙酰胆碱受体亚单位选择性阻断剂，可显著阻断尼古丁对小胶质细胞激活和TH-IP神经元丢失的抑制作用。大鼠慢性尼古丁预处理后，内毒素刺激所致黑质TH-IP神经元丢失明显减少，并伴有肿瘤坏死因子-α的生成减少。本研究表明尼古丁对多巴胺能神经元具有神经保护作用，其机制是通过调节小胶质细胞的激活来实现的。结合尼古丁的多种神经保护作用，尼古丁的抗炎机制可能在帕金森病的预防治疗中具有重要的治疗意义。
Epidemiological studies have reported that smoking is associated with a lower incidence of Parkinson's disease (PD), leading to theories that smoking in general and nicotine in particular might be neuroprotective. Recent studies suggested cholinergic anti-inflammatory pathway-regulating microglial activation through alpha 7 nicotinic receptors. In the present study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether nicotine has a protective effect on the dopaminergic system through an anti-inflammatory mechanism. Nicotine pretreatment considerably decreased microglial activation with significant reduction of tumour necrosis factor (TNF)-alpha mRNA expression and TNF-alpha release induced by LPS stimulation. In co-cultures of microglia and mesencephalic neurons, nicotine pretreatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells, approximately twice more than the LPS-only treatment. alpha-Bungarotoxin, an alpha 7 nicotinic acetylcholine receptor subunit-selective blocker, considerably blocked the inhibitory effects of nicotine on microglial activation and TH-ip neuronal loss. Chronic nicotine pretreatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the substantia nigra was dramatically decreased, which was clearly accompanied by a reduction in the formation of TNF-alpha. The present study demonstrated that nicotine has a neuroprotective effect on dopaminergic neurons via an anti-inflammatory mechanism mediated by the modulation of microglial activation. Along with various neuroprotective effects of nicotine, the anti-inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD.