The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an in Vitro Model of Alzheimer Disease

被引:31
作者
Alonso, Eva [1 ]
Vale, Carmen [1 ]
Vieytes, Mercedes R. [2 ]
Laferla, Frank M. [3 ]
Gimenez-Llort, Lydia [4 ]
Botana, Luis M. [1 ]
机构
[1] Univ Santiago de Compostela, Fac Vet, Dpto Farmacol, Lugo 27003, Spain
[2] Univ Santiago de Compostela, Fac Vet, Dept Fisiol, Lugo 27003, Spain
[3] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA USA
[4] Univ Autonoma Barcelona, Inst Neurosci, Dept Psychiat & Forens Med, Bellaterra, Spain
关键词
Gymnodimine; Alzheimer disease; Tau protein; Beta-amyloid; Acetylcholine; NICOTINIC ACETYLCHOLINE-RECEPTOR; HIGH-AFFINITY; MUSCARINIC RECEPTOR; CORTICAL-NEURONS; CALCIUM; BINDING; PHOSPHORYLATION; IMPAIRMENT; BRAIN; HYPOTHESIS;
D O I
10.1159/000330086
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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
引用
收藏
页码:783 / 794
页数:12
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