α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation.
α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation.
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在MPTP小鼠模型中，α7烟碱乙酰胆碱受体介导的对多巴胺能神经元丧失的神经保护通过抑制星形胶质细胞激活。
DOI：
10.1186/1742-2094-9-98
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发表时间：
2012-05-24
影响因子：
9.3
通讯作者：
Fan W
中科院分区：
文献类型：
--
作者：
Liu Y;Hu J;Wu J;Zhu C;Hui Y;Han Y;Huang Z;Ellsworth K;Fan W
尽管有证据表明吸烟者的帕金森氏病(PD)患病率低于非吸烟者，但尼古丁诱导的神经保护机制仍不清楚。刺激α7烟碱型乙酰胆碱受体(α7-nAChR)似乎是胆碱能激动剂在免疫细胞(包括星形胶质细胞)中抗炎的重要机制，抑制星形胶质细胞的激活已被认为是治疗帕金森病等神经退行性疾病的新策略。本研究的目的是确定尼古丁对1-甲基-4-苯基-1，2，3，6-四氢吡啶小鼠模型的神经保护作用是否通过α7-nAChR介导的星形胶质细胞抑制而发生。采用体内和体外(1-甲基-4-苯基吡啶离子和脂多糖)帕金森病模型，观察α-7-nAChRs对多巴胺能神经元损伤的保护作用(S)及其可能机制(S)。采用行为学、免疫化学和体视学实验、星形胶质细胞培养、逆转录酶聚合酶链式反应、激光扫描共聚焦显微镜、肿瘤坏死因子α分析和免疫印迹等多种实验方法，对α7-nAChR介导的神经保护机制进行了研究。全身应用尼古丁可减轻MPTP诱导的行为症状，改善运动协调性，并防止黑质多巴胺能神经元丢失和星形胶质细胞和小胶质细胞的激活。尼古丁的保护作用可被α7-nAChR选择性拮抗剂甲基莲心乌头碱所消除。在原代培养的小鼠星形胶质细胞中，尼古丁可抑制MPP+或脂多糖诱导的星形胶质细胞的激活，表现为肿瘤坏死因子α的产生减少，并抑制星形胶质细胞的细胞外调节激酶1/2(ERK1/2)和p38的激活，这些作用也被MLA逆转。综上所述，我们的结果提示α7-nAChR介导的抑制星形胶质细胞激活是尼古丁保护作用的重要机制。
Although evidence suggests that the prevalence of Parkinson’s disease (PD) is lower in smokers than in non-smokers, the mechanisms of nicotine-induced neuroprotection remain unclear. Stimulation of the α7 nicotinic acetylcholine receptor (α7-nAChR) seems to be a crucial mechanism underlying the anti-inflammatory potential of cholinergic agonists in immune cells, including astrocytes, and inhibition of astrocyte activation has been proposed as a novel strategy for the treatment of neurodegenerative disorders such as PD. The objective of the present study was to determine whether nicotine-induced neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model occurs via α7-nAChR-mediated inhibition of astrocytes. Both in vivo (MPTP) and in vitro (1-methyl-4-phenylpyridinium ion (MPP+) and lipopolysaccharide (LPS)) models of PD were used to investigate the role(s) of and possible mechanism(s) by which α7-nAChRs protect against dopaminergic neuron loss. Multiple experimental approaches, including behavioral tests, immunochemistry, and stereology experiments, astrocyte cell cultures, reverse transcriptase PCR, laser scanning confocal microscopy, tumor necrosis factor (TNF)-α assays, and western blotting, were used to elucidate the mechanisms of the α7-nAChR-mediated neuroprotection. Systemic administration of nicotine alleviated MPTP-induced behavioral symptoms, improved motor coordination, and protected against dopaminergic neuron loss and the activation of astrocytes and microglia in the substantia nigra. The protective effects of nicotine were abolished by administration of the α7-nAChR-selective antagonist methyllycaconitine (MLA). In primary cultured mouse astrocytes, pretreatment with nicotine suppressed MPP+-induced or LPS-induced astrocyte activation, as evidenced by both decreased production of TNF-α and inhibition of extracellular regulated kinase1/2 (Erk1/2) and p38 activation in astrocytes, and these effects were also reversed by MLA. Taken together, our results suggest that α7-nAChR-mediated inhibition of astrocyte activation is an important mechanism underlying the protective effects of nicotine.
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影响因子：
3.4
作者：
Park, Hyun Jung;Lee, Phil Hyu;Jin, Byung Kwan
通讯作者：
Jin, Byung Kwan
影响因子：
4.2
作者：
WEST, MJ
通讯作者：
WEST, MJ
影响因子：
3
作者：
TUREK, JW;KANG, CH;SULLIVAN, JP
通讯作者：
SULLIVAN, JP
Iptakalim 可防止 MPP 诱导的与星形胶质细胞激活相关的多巴胺能神经元变性。
DOI：
10.1017/s1461145708009243
发表时间：
2009-04-01
影响因子：
4.8
作者：
Yang, Yan-Jing;Zhang, Shu;Hu, Gang
通讯作者：
Hu, Gang
影响因子：
5.3
作者：
Furuya, T;Hayakawa, H;Mochizuki, H
通讯作者：
Mochizuki, H