PDF(Pubmed)
Abstract：
In multiple sclerosis (MS), mitochondrial alterations appear to contribute to disease progression. The sphingosine-1-phosphate receptor modulator siponimod is approved for treating secondary progressive MS. Its preceding compound fingolimod was shown to prevent oxidative stress-induced alterations in mitochondrial morphology. Here, we assessed the effects of siponimod, compared to fingolimod, on neuronal mitochondria in oxidatively stressed hippocampal slices. We have also advanced the model of chronic organotypic hippocampal slices for live imaging, enabling semi-automated monitoring of mitochondrial alterations. The slices were prepared from B6.Cg-Tg(Thy1-CFP/COX8A)S2Lich/J mice that display fluorescent neuronal mitochondria. They were treated with hydrogen peroxide (oxidative stress paradigm) ± 1 nM siponimod or fingolimod for 24 h. Afterwards, mitochondrial dynamics were investigated. Under oxidative stress, the fraction of motile mitochondria decreased and mitochondria were shorter, smaller, and covered smaller distances. Siponimod partly prevented oxidatively induced alterations in mitochondrial morphology; for fingolimod, a similar trend was observed. Siponimod reduced the decrease in mitochondrial track displacement, while both compounds significantly increased track speed and preserved motility. The novel established imaging and analysis tools are suitable for assessing the dynamics of neuronal mitochondria ex vivo. Using these approaches, we showed that siponimod at 1 nM partially prevented oxidatively induced mitochondrial alterations in chronic brain slices.
摘要：
在多发性硬化症（MS）中，线粒体改变似乎有助于疾病进展。鞘氨醇-1-磷酸受体调节剂西波莫德被批准用于治疗继发性进行性MS。其先前的化合物芬戈莫德被证明可以防止氧化应激诱导的线粒体形态改变。这里,我们评估了西波莫德的作用,与芬戈莫德相比,在氧化应激海马切片中的神经元线粒体上。我们还改进了用于实时成像的慢性器官型海马切片模型，实现线粒体改变的半自动监测。从B6制备切片。显示荧光神经元线粒体的Cg-Tg(Thy1-CFP/COX8A)S2lich/J小鼠。用过氧化氢（氧化应激范例）±1nM西波莫德或芬戈莫德处理24小时。之后，线粒体动力学进行了研究。在氧化应激下，活动线粒体的比例下降，线粒体变短，更小,覆盖较小的距离。Siponimod部分阻止线粒体形态的氧化诱导改变；对于芬戈莫德，观察到类似的趋势。Siponimod减少了线粒体径迹位移的减少，而这两种化合物都显着提高了履带速度并保持了运动性。新建立的成像和分析工具适用于评估离体神经元线粒体的动力学。使用这些方法，我们发现辛波莫德在1nM时部分阻止了慢性脑切片中氧化诱导的线粒体改变。
