Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Crit Rev Biochem Mol Biol. 2011 Feb;46(1):2-10. doi: 10.3109/10409238.2010.522975. Epub 2010 Oct 28.
Sphingosine 1-phosphate (S1P) signaling in the treatment of multiple sclerosis (MS) has been highlighted by the efficacy of FTY720 (fingolimod), which upon phosphorylation can modulate S1P receptor activities. FTY720 has become the first oral treatment for relapsing MS that was approved by the FDA in September 2010. Phosphorylated FTY720 modulates four of the five known S1P receptors (S1P(1), S1P(3), S1P(4), and S1P(5)) at high affinity. Studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have revealed that FTY720 exposure alters lymphocyte trafficking via sequestration of auto-aggressive lymphocytes within lymphoid organs, representing the current understanding of its mechanism of action. These effects primarily involve S1P(1), which is thought to attenuate inflammatory insults in the central nervous system (CNS). In addition, FTY720's actions may involve direct effects on S1P receptor-mediated signaling in CNS cells, based upon the known expression of S1P receptors in CNS cell types relevant to MS, access to the CNS through the blood-brain barrier (BBB), and in vitro studies. These data implicate lysophospholipid signaling--via S1P(1) and perhaps other lysophospholipid receptors--in therapeutic approaches to MS and potentially other diseases with immunological and/or neurological components.
鞘氨醇 1-磷酸（S1P）信号在多发性硬化症（MS）的治疗中得到了强调，因为 FTY720（fingolimod）的疗效，它在磷酸化后可以调节 S1P 受体的活性。FTY720 已成为 2010 年 9 月 FDA 批准的第一种用于治疗复发性多发性硬化症的口服药物。磷酸化 FTY720 以高亲和力调节五种已知的 S1P 受体（S1P(1)、S1P(3)、S1P(4)和 S1P(5))中的四种。在人类 MS 及其动物模型实验性自身免疫性脑脊髓炎（EAE）中的研究表明，FTY720 的暴露通过将自身攻击性淋巴细胞隔离在淋巴器官内来改变淋巴细胞的迁移，这代表了其作用机制的当前理解。这些作用主要涉及 S1P(1)，它被认为可以减轻中枢神经系统（CNS）中的炎症损伤。此外，基于与 MS 相关的 CNS 细胞类型中 S1P 受体的已知表达、通过血脑屏障（BBB）进入 CNS 以及体外研究，FTY720 的作用可能涉及 S1P 受体介导的 CNS 细胞信号转导的直接作用。这些数据表明，溶血磷脂信号--通过 S1P(1)和其他可能的溶血磷脂受体--参与了多发性硬化症和潜在的其他具有免疫和/或神经成分的疾病的治疗方法。
