Central nervous system-directed effects of FTY720 (fingolimod)
Central nervous system-directed effects of FTY720 (fingolimod)
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DOI：
10.1016/j.jns.2008.06.031
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发表时间：
2008-11-15
影响因子：
4.4
通讯作者：
Antel, Jack P.
中科院分区：
文献类型：
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作者：
Miron, Veronique E.;Schubart, Anna;Antel, Jack P.
FTY720，也称为Fingolimod，是一种口服1-磷酸鞘氨醇(SI P)类似物，正在研究中，用于治疗复发-缓解(RR)和进展型多发性硬化症(MS)。FTY720对RR-MS患者和实验性自身免疫性脑脊髓炎(EAE)动物模型疾病活动性的有益效果很大程度上归因于对系统免疫系统的影响。此外，与目前用于治疗多发性硬化症的其他系统免疫调节剂不同，FTY720的亲脂性使其能够穿过血脑屏障(BBB)。由于S1P受体在所有类型的细胞中都有表达，FTY720有可能直接作用于血脑屏障和中枢神经系统的驻留细胞。后者包括参与调节中枢神经系统内免疫反应的细胞(星形胶质细胞、小胶质细胞)，那些作为疾病过程靶标的细胞(少突胶质细胞、神经元)，以及那些参与修复的细胞(少突胶质前体细胞)。体外研究记录了FTY720对神经细胞存活、分化和细胞骨架动力学的剂量依赖效应。动物模型研究，特别是EAE，表明FTY720的整体神经保护作用至少部分通过其在中枢神经系统内的作用而调节。正在进行的研究将需要确定FTY720在MS(C)2008 Elsevier B.V.的广泛临床范围内对中枢神经系统的直接和间接影响(通过免疫调节)。保留所有权利。
FTY720, also known as fingolimod, is an orally administered sphingosine-1-phosphate (SI P) analogue that is under investigation as a therapy for both relapsing-remitting (RR) and progressive forms of multiple sclerosis (MS). The demonstrated beneficial effect of FTY720 on disease activity in RR-MS patients and in the animal model experimental autoimmune encephalomyelitis (EAE) is largely attributed to effects on the systemic immune system. In addition, unlike other Current systemic immuno-modulators used in MS, the lipophilic nature of FTY720 allows it to cross the blood-brain barrier (BBB). Since S1P receptors are expressed oil all cell types, FTY720 has the potential to exert effects directly on the BBB and on resident cells of the CNS. The latter include cells implicated in regulating immune reactivity within the CNS (astrocytes, microglia), those that are targeted by the disease process (oligodendrocytes, neurons), and those involved in repair (oligodendrocyte progenitor cells). In vitro studies document the dose-dependent effects of FTY720 on neural cell survival, differentiation, and cytoskeletal dynamics. Animal model studies, specifically EAE, indicate an overall neuroprotective effect of FTY720 mediated at least in part by its actions within the CNS. Ongoing studies will need to define the direct and indirect (via immune-modulation) effects of FTY720 on the CNS across the broad clinical spectrum of MS. (C) 2008 Elsevier B.V. All rights reserved.