Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway.
LIED, University of Lübeck, Lübeck, Germany.
Drugs R D. 2020 Sep;20(3):197-207. doi: 10.1007/s40268-020-00316-1.
Fingolimod is an approved treatment for relapsing-remitting multiple sclerosis (MS), and its properties in different pathways have raised interest in therapy research for other neurodegenerative diseases. Fingolimod is an agonist of sphingosine-1-phosphate (S1P) receptors. Its main pharmacologic effect is immunomodulation by lymphocyte homing, thereby reducing the numbers of T and B cells in circulation. Because of the ubiquitous expression of S1P receptors, other effects have also been described. Here, we review preclinical experiments evaluating the effects of treatment with fingolimod in neurodegenerative diseases other than MS, such as Alzheimer's disease or epilepsy. Fingolimod has shown neuroprotective effects in different animal models of neurodegenerative diseases, summarized here, correlating with increased brain-derived neurotrophic factor and improved disease phenotype (cognition and/or motor abilities). As expected, treatment also induced reductions in different neuroinflammatory markers because of not only inhibition of lymphocytes but also direct effects on astrocytes and microglia. Furthermore, fingolimod treatment exhibited additional effects for specific neurodegenerative disorders, such as reduction of amyloid-β production, and antiepileptogenic properties. The neuroprotective effects exerted by fingolimod in these preclinical studies are reviewed and support the translation of fingolimod into clinical trials as treatment in neurodegenerative diseases beyond neuroinflammatory conditions (MS).
芬戈莫德是一种已获批用于治疗复发缓解型多发性硬化症（MS）的药物，其在不同途径中的特性引起了人们对其他神经退行性疾病治疗研究的兴趣。芬戈莫德是鞘氨醇-1-磷酸（S1P）受体的激动剂。其主要的药理作用是通过淋巴细胞归巢来调节免疫，从而减少循环中的 T 和 B 细胞数量。由于 S1P 受体广泛表达，因此也描述了其他作用。在这里，我们综述了评估芬戈莫德在除 MS 以外的神经退行性疾病中的治疗效果的临床前实验，如阿尔茨海默病或癫痫。芬戈莫德在不同的神经退行性疾病动物模型中显示出神经保护作用，如增加脑源性神经营养因子和改善疾病表型（认知和/或运动能力）。正如预期的那样，由于不仅抑制淋巴细胞，而且直接作用于星形胶质细胞和小胶质细胞，治疗还导致不同神经炎症标志物的减少。此外，芬戈莫德治疗还表现出针对特定神经退行性疾病的额外作用，如减少淀粉样蛋白-β的产生和抗癫痫作用。我们综述了芬戈莫德在这些临床前研究中发挥的神经保护作用，并支持将芬戈莫德转化为临床试验，作为神经退行性疾病（而非神经炎症性疾病）的治疗方法。
