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lüll FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system Brinkmann VBr J Pharmacol 2009[Nov]; 158 (5): 1173-82FTY720 (fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that was highly effective in Phase II clinical trials for Multiple Sclerosis (MS). FTY720 is phosphorylated in vivo by sphingosine kinase-2 to form the active moiety FTY720-phosphate that binds to four of the five G protein-coupled S1P receptor subtypes. Studies using conditional S1P1 receptor-deficient and sphingosine kinase-deficient mice showed that the egress of lymphocytes from lymph nodes requires signalling of lymphocytic S1P1 receptors by the endogenous ligand S1P. The S1P mimetic FTY720-phosphate causes internalization and degradation of cell membrane-expressed S1P1, thereby antagonizing S1P action at the receptor. In models of human MS and demyelinating polyneuropathies, functional antagonism of lymphocytic S1P1 slows S1P-driven egress of lymphocytes from lymph nodes, thereby reducing the numbers of autoaggressive TH17 cells that recirculate via lymph and blood to the central nervous system and the sciatic/ischiatic nerves. Based on its lipophilic nature, FTY720 crosses the blood-brain barrier, and ongoing experiments suggest that the drug also down-modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap-junctional communication of astrocytes with neurons and cells of the blood-brain barrier. Additional effects may result from (down-) modulation of S1P3 in astrocytes and of S1P1 and S1P5 in oligodendrocytes. In conclusion, FTY720 may act through immune-based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma. Beyond the autoimmune indications, very recent studies suggest that short-term, low-dose administration of FTY720 could help treat chronic (viral) infections. Differential effects of the drug on the trafficking of naive, central memory and effector memory T cell subsets are discussed.|Animals[MESH]|Astrocytes/immunology/pathology[MESH]|Brain/*drug effects[MESH]|Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology[MESH]|Fingolimod Hydrochloride[MESH]|Gap Junctions/physiology[MESH]|Humans[MESH]|Immune System/*drug effects[MESH]|Inflammation/immunology[MESH]|Lymph Nodes/immunology/pathology[MESH]|Lysophospholipids/physiology[MESH]|Multiple Sclerosis/*drug therapy/*immunology[MESH]|Phosphorylation[MESH]|Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism[MESH]|Propylene Glycols/pharmacology/*therapeutic use[MESH]|Receptors, Lysosphingolipid/*antagonists & inhibitors/genetics/physiology[MESH]|Sphingosine/*analogs & derivatives/pharmacology/physiology/therapeutic use[MESH]|T-Lymphocytes/physiology[MESH] |