Abstract
FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional “antagonist” and “agonist” mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.
Highlights
FTY720 (Fingolimod) was originally synthesized by a group of Japanese researchers in 1992 while investigating structure-activity relationships in derivatives of the fungal metabolite myriocin (ISP-I), which was isolated from Isaria sinclairii [1]
Functional agonistic mechanisms are executed through S1P receptors expressed on the membrane surfaces of cells including neurons, astrocytes, microglia, and vessel endothelial cells
FTY720-P binds to four of the five known G protein-coupled S1P receptors (S1P1, S1P3–5), which results in the activation of its downstream pathways via the transduction of G protein isoforms
Summary
FTY720 (Fingolimod) was originally synthesized by a group of Japanese researchers in 1992 while investigating structure-activity relationships in derivatives of the fungal metabolite myriocin (ISP-I), which was isolated from Isaria sinclairii [1]. FTY720 shows strong immunosuppressive potential and was approved as the first oral immunomodulatory drug for multiple sclerosis (MS) by the United States food and drug administration (FDA) in 2010 It is catalyzed by sphingosine kinase (SphK) to its physiologically active phosphorylated form (FTY720-P), and this acts as a high-affinity agonist of Sphingosine-1-phosphate (S1P). The functional antagonistic mechanisms are mediated by the temporary down-regulation and degradation of S1P receptors on lymphocytes, which prevents these cells from entering the blood stream from the lymph node. To better understand its activity, it is important to elucidate the mechanisms associated with FTY720 and S1P receptors, and the metabolic and functional mechanisms related to the original ligand, S1P, and its metabolites and enzymes including sphingosine, ceramide, and. S1P is catalyzed into hexadecenal and phosphoethanolamine by the S1P-lyase
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