The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an in Vitro Model of Alzheimer Disease
The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an in Vitro Model of Alzheimer Disease
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DOI：
10.1159/000330086
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发表时间：
2011-01-01
影响因子：
--
通讯作者：
Botana, Luis M.
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文献类型：
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作者：
Alonso, Eva;Vale, Carmen;Botana, Luis M.
裸子二胺（Gymnodimine， GYM）是一种具有大环亚胺结构的海洋藻毒素，从鞭毛藻Karenia selliforma的提取物中分离出来，是一种具有亚型选择性的胆碱能拮抗剂。然而，到目前为止，还没有关于这种化合物的慢性影响的数据报道。在这项工作中，我们评估了皮质神经元长期暴露于裸子二胺对阿尔茨海默病（AD）病理进展的影响。用50 nM裸子二胺处理皮质神经元可降低细胞内β淀粉样蛋白（A β）的积累和AT8和AT100抗体识别的tau蛋白高磷酸化亚型的水平。这些结果被认为是由糖原合成酶激酶-3（磷酸化GSK-3 Ser9）的无活性异构体增加、ERK1/2激酶活性异构体水平下降和皮质神经元长期暴露于毒素引起的乙酰胆碱（Ach）合成增加所介导的。此外，裸子二胺在体外降低谷氨酸诱导的神经毒性。总之，这些结果表明，海洋藻毒素裸子二胺可能为开发治疗神经退行性疾病的药物提供了有价值的工具。巴塞尔S. Karger股份有限公司版权所有
Gymnodimine (GYM) is a marine phycotoxin with a macrocyclic imine structure, isolated from extracts of the dinoflagellate Karenia selliformis known to act as a cholinergic antagonist with subtype selectivity. However, no data on the chronic effects of this compound has been reported so far. In this work, we evaluated the effect of long term exposure of cortical neurons to gymnodimine in the progress of Alzheimer disease (AD) pathology in vitro. Treatment of cortical neurons with 50 nM gymnodimine decreased the intracellular amyloid beta (A beta) accumulation and the levels of the hyperphosphorylated isoforms of tau protein recognized by AT8 and AT100 antibodies. These results are suggested to be mediated by the increase in the inactive isoform of the glycogen synthase kinase-3 (phospho GSK-3 Ser9), the decrease in the levels of the active isoform of the ERK1/2 kinase and the increase in acetylcholine (Ach) synthesis elicited by long term exposure of cortical neurons to the toxin. Moreover, gymnodimine decreased glutamate-induced neurotoxicity in vitro. Altogether these results indicate that the marine phycotoxin gymnodimine may constitute a valuable tool for the development of drugs to treat neurodegenerative diseases. Copyright (C) 2011 S. Karger AG, Basel