Galantamine modulates nicotinic receptor and blocks Aβ-enhanced glutamate toxicity
Galantamine modulates nicotinic receptor and blocks Aβ-enhanced glutamate toxicity
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DOI：
10.1016/j.bbrc.2004.10.132
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发表时间：
2004-12-17
影响因子：
3.1
通讯作者：
Shimohama, S
中科院分区：
文献类型：
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作者：
Kihara, T;Sawada, H;Shimohama, S
加兰他明是一种植物生物碱，用于治疗阿尔茨海默病。我们利用原代培养的大鼠皮质神经元研究了加兰他明对β-淀粉样蛋白增强的谷氨酸毒性的影响。尼古丁和加兰他明单独和联合使用，可以保护神经元免受这种神经毒性的影响。α4β2烟碱型乙酰胆碱受体(NAChR)拮抗剂不阻断这种保护作用，但可被0 nAChR拮抗剂部分阻断。加兰他明可诱导磷脂酰肌醇3-激酶(PI3K)的效应蛋白Akt的磷酸化，而PI3K抑制剂可阻断这种保护作用和Akt的磷酸化。抗体FK1选择性地阻断了nAChR上变构增强的配体位点，显著降低了加兰他明诱导的保护和Akt的磷酸化。此外，使用RNA干扰技术抑制0nAChR可减少加兰他明诱导的Akt磷酸化。我们的数据表明，加兰他明的神经保护作用至少部分是通过α7nAChR-PI3K级联反应介导的。(C)2004 Elsevier Inc.保留所有权利。
Galantamine is a plant alkaloid that is used in the treatment of Alzheimer's disease. We have studied the effects of galantamine on beta-amyloid-enhanced glutamate toxicity using primary rat cultured cortical neurons. Nicotine and galantamine alone, and in combination, protected neurons against this neurotoxicity. The protection was not blocked by alpha4beta2 nicotinic acetylcholine receptor (nAChR) antagonists, but was partially blocked by 0 nAChR antagonists. Galantamine induced phosphorylation of Akt, an effector of phosphatidylinositol 3-kinase (PI3K), while PI3K inhibitors blocked the protective effect and Akt phosphorylation. The antibody FK1, which selectively blocks the allosterically potentiating ligand site on nAChR, significantly reduced the galantamine-induced protection and Akt phosphorylation. Furthermore, suppression of 0 nAChR using an RNA interference technique reduced Akt phosphorylation induced by galantamine. Our data suggest that neuroprotection by galantamine is mediated, at least in part, by alpha7 nAChR-PI3K cascade. (C) 2004 Elsevier Inc. All rights reserved.