Fingolimod for the treatment of neurological diseases-state of play and future perspectives.
Fingolimod for the treatment of neurological diseases-state of play and future perspectives.
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DOI：
10.3389/fncel.2014.00283
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发表时间：
2014
影响因子：
5.3
通讯作者：
Pfeilschifter W
中科院分区：
文献类型：
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作者：
Brunkhorst R;Vutukuri R;Pfeilschifter W
鞘脂是一类由鞘磷脂膜脂衍生而来的令人着迷的信号分子。它们在大脑中表现出丰富的表达。复杂鞘脂，如鞘脂糖（神经节苷和脑苷）调节囊泡运输和溶酶体降解，其失调可导致具有神经表型的储存性疾病。最近，神经酰胺、鞘氨醇和鞘氨醇1-磷酸（S1P）等简单鞘脂被发现对许多细胞外刺激发出信号。形成一个复杂的信号网络，这些容易互换的介质的平衡对应激条件下细胞的命运是决定性的。免疫调节剂fingolimod是一种S1P受体激动剂的前药。受体激活后，该药物导致S1P1受体下调，诱导功能性拮抗。作为第一种调节鞘脂信号通路的药物，它于2010年上市，用于治疗多发性硬化症（MS）。当时，免疫调节被广泛认为是芬戈莫德治疗多发性硬化症的关键机制，但考虑到这种亲脂性化合物进入大脑的良好通道及其在大脑中的大量积累，以及脑细胞上丰富的S1P受体表达，可以想象芬戈莫德也直接作用于脑细胞。事实上，一项重要的研究表明，芬戈莫德对实验性自身免疫性脑炎（EAE）的保护作用在星形胶质细胞缺乏S1P1受体的小鼠中消失，这表明星形胶质细胞S1P信号通路在MS中起着特定的作用。本文将讨论鞘脂介质及其代谢酶在神经系统疾病中的作用以及由此产生的可能的治疗策略。
Sphingolipids are a fascinating class of signaling molecules derived from the membrane lipid sphingomyelin. They show abundant expression in the brain. Complex sphingolipids such as glycosphingolipids (gangliosides and cerebrosides) regulate vesicular transport and lysosomal degradation and their dysregulation can lead to storage diseases with a neurological phenotype. More recently, simple sphingolipids such ceramide, sphingosine and sphingosine 1-phosphate (S1P) were discovered to signal in response to many extracellular stimuli. Forming an intricate signaling network, the balance of these readily interchangeable mediators is decisive for cell fate under stressful conditions. The immunomodulator fingolimod is the prodrug of an S1P receptor agonist. Following receptor activation, the drug leads to downregulation of the S1P1 receptor inducing functional antagonism. As the first drug to modulate the sphingolipid signaling pathway, it was marketed in 2010 for the treatment of multiple sclerosis (MS). At that time, immunomodulation was widely accepted as the key mechanism of fingolimod’s efficacy in MS. But given the excellent passage of this lipophilic compound into the brain and its massive brain accumulation as well as the abundant expression of S1P receptors on brain cells, it is conceivable that fingolimod also affects brain cells directly. Indeed, a seminal study showed that the protective effect of fingolimod in experimental autoimmune encephalitis (EAE), a murine MS model, is lost in mice lacking the S1P1 receptor on astrocytes, arguing for a specific role of astrocytic S1P signaling in MS. In this review, we discuss the role of sphingolipid mediators and their metabolizing enzymes in neurologic diseases and putative therapeutic strategies arising thereof.
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影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR
影响因子：
3.1
作者：
Asle-Rousta, Masoumeh;Kolahdooz, Zeynab;Dargahi, Leila
通讯作者：
Dargahi, Leila
影响因子：
3.4
作者：
Arboleda, Gonzalo;Huang, Tze-Jen;Gibson, Rosemary M.
通讯作者：
Gibson, Rosemary M.
DOI：
10.1073/pnas.94.20.10873
发表时间：
1997-09-30
影响因子：
11.1
作者：
Becker, KJ;McCarron, RM;Hallenbeck, JM
通讯作者：
Hallenbeck, JM
影响因子：
64.8
作者：
通讯作者：
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