Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Facultad de Veterinaria , Universidad de Santiago de Compostela , 27001 Lugo , Spain.
Departamento de Fisiología, Facultad de Veterinaria , Universidad de Santiago de Compostela , 27001 Lugo , Spain.
ACS Chem Neurosci. 2018 Jun 20;9(6):1441-1452. doi: 10.1021/acschemneuro.8b00036. Epub 2018 Mar 14.
Spirolides (SPX) are marine toxins, produced by dinoflagellates that act as potent antagonists of nicotinic acetylcholine receptors. These compounds are not toxic for humans, and since there are no reports of human intoxications caused by this group of toxins they are not yet currently regulated in Europe. Currently 13-desmethyl spirolide C, 13,19-didesmethyl spirolide C, and 20-methyl spirolide G are commercially available as reference materials. Previous work in our laboratory has demonstrated that after 4 days of treatment of primary mice cortical neurons with 13-desmethyl spirolide C, the compound ameliorated the glutamate induced toxicity and increased acetylcholine levels and the expression of the acetylcholine synthesizing enzyme being useful both in vitro and in vivo to decrease the brain pathology associated with Alzheimer's disease. In this work, we aimed to extend the study of the neuronal effects of spirolides in human neuronal cells. To this end, human neuronal progenitor cells CTX0E16 were employed to evaluate the in vitro effect of spirolides on neuronal development. The results presented here indicate that long-term exposure (30 days) of human neuronal stem cells to SPX compounds, at concentrations up to 50 nM, ameliorated the MPP-induced neurotoxicity and increased the expression of neuritic and dendritic markers, the levels of the choline acetyltransferase enzyme and the protein levels of the α7 subunit of nicotinic acetylcholine receptors. These effects are presumably due to the previously described interaction of these compounds with nicotinic receptors containing both α7 and α4 subunits. All together, these data emphasize the idea that SPX could be attractive lead molecules against neurodegenerative disorders.
螺旋内酯（SPX）是海洋毒素，由甲藻产生，作为烟碱型乙酰胆碱受体的有效拮抗剂。这些化合物对人类没有毒性，由于没有关于人类因该毒素组中毒的报告，因此它们目前在欧洲尚未受到监管。目前，13-去甲基螺旋内酯 C、13,19-二去甲基螺旋内酯 C 和 20-甲基螺旋内酯 G 可作为商业参考物质使用。我们实验室之前的工作表明，在原代小鼠皮质神经元用 13-去甲基螺旋内酯 C 处理 4 天后，该化合物减轻了谷氨酸诱导的毒性，增加了乙酰胆碱水平，并表达了乙酰胆碱合成酶，无论是在体外还是体内，都有助于减少与阿尔茨海默病相关的脑病理学。在这项工作中，我们旨在扩展对人类神经元细胞中螺旋内酯神经作用的研究。为此，使用人类神经祖细胞 CTX0E16 来评估螺旋内酯对神经元发育的体外影响。这里呈现的结果表明，SPX 化合物长期（30 天）暴露于浓度高达 50 nM 的人类神经干细胞，减轻了 MPP 诱导的神经毒性，并增加了神经突和树突标记物的表达、胆碱乙酰转移酶酶的水平和烟碱型乙酰胆碱受体的α7 亚基的蛋白水平。这些作用可能是由于这些化合物先前描述的与含有α7 和α4 亚基的烟碱受体相互作用所致。所有这些数据都强调了 SPX 可能是对抗神经退行性疾病的有吸引力的先导分子的想法。
