Valero Teresa, del Barrio Laura, Egea Javier, Cañas Noelia, Martínez Ana, García Antonio G, Villarroya Mercedes, López Manuela G
Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain.
Eur J Pharmacol. 2009 Apr 1;607(1-3):47-53. doi: 10.1016/j.ejphar.2009.02.021. Epub 2009 Feb 21.
Marine sponges are becoming a rich source of potential new medicines. NP04634 is a synthetic derivative of 11,19 dideoxyfistularin, a natural product of the Mediterranean sponge Aplysina cavernicola. We report the cytoprotective effects of this new compound in isolated bovine chromaffin cells exposed to cytotoxic stimuli that have been related to neuronal cell death, i.e. Ca(2+) overload and mitochondrial dysfunction. Cell death was achieved by: (i) causing Ca(2+) overload through voltage-dependent calcium channels by exposing the cells to 30 mM K(+), 5 mM Ca(2+) plus 0.3 microM FPL64176 (an L-type Ca(2+)-channel activator); (ii) incubating the cells with veratridine, causing cytosolic Ca(2+) concentration (Ca(2+)) oscillations and mitochondrial disruption; and (iii) blocking mitochondrial complexes I and V using a combination of 30 microM rotenone and 10 microM oligomycin. At 10 microM, NP04634 caused significant protection against 30K(+)/5Ca(2+)/FPL-induced toxicity. NP04634 caused a concentration-dependent reduction in Ca(2+) induced by 70 mM K(+) in cells loaded with Fluo-4; maximum blockade was 67% at 30 microM. Veratridine caused continuous Ca(2+) oscillations that translated into 43.4+/-2% cell death. In this model, NP04634 caused 42% and 67% protection at 3 and 10 microM, respectively. NP04634 reduced Ca(2+) oscillations and mitochondrial depolarization caused by veratridine. NP04634 at 10 microM also protected against mitochondrial disruption caused by rotenone plus oligomycin. In conclusion, NP04634 is a novel compound of marine origin with cytoprotective properties that might have potential therapeutic implications under pathological circumstances involving Ca(2+) overload and mitochondrial disruption, such as in certain neurodegenerative diseases and/or stroke.
海洋海绵正成为潜在新药物的丰富来源。NP04634是11,19 - 二脱氧岩沙海葵毒素的合成衍生物，11,19 - 二脱氧岩沙海葵毒素是地中海海绵Aplysina cavernicola的一种天然产物。我们报告了这种新化合物在分离的牛嗜铬细胞中的细胞保护作用，这些细胞暴露于与神经元细胞死亡相关的细胞毒性刺激下，即钙离子过载和线粒体功能障碍。通过以下方式诱导细胞死亡：(i) 将细胞暴露于30 mM钾离子、5 mM钙离子加0.3 microM FPL64176（一种L型钙离子通道激活剂），通过电压依赖性钙离子通道导致钙离子过载；(ii) 用藜芦碱孵育细胞，引起胞质钙离子浓度（Ca(2+)）振荡和线粒体破坏；(iii) 联合使用30 microM鱼藤酮和10 microM寡霉素阻断线粒体复合物I和V。在10 microM时，NP04634对30K(+)/5Ca(2+)/FPL诱导的毒性具有显著保护作用。NP04634使加载了Fluo - 4的细胞中由70 mM钾离子诱导的Ca(2+)呈浓度依赖性降低；在30 microM时最大阻断率为67%。藜芦碱引起持续的Ca(2+)振荡，导致43.4±2%的细胞死亡。在该模型中，NP04634在3 microM和10 microM时分别提供了42%和67%的保护作用。NP04634减少了藜芦碱引起的Ca(2+)振荡和线粒体去极化。10 microM的NP04634还对鱼藤酮加寡霉素引起的线粒体破坏具有保护作用。总之，NP04634是一种具有细胞保护特性的新型海洋来源化合物，在涉及钙离子过载和线粒体破坏的病理情况下，如某些神经退行性疾病和/或中风，可能具有潜在的治疗意义。
