title: Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.
abstract: OBJECTIVE
  Effect of fingolimod in multiple sclerosis (MS) is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB). However, brain microvascular endothelial cells (BMECs) represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera.
  
  
  METHODS
  Changes in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER) in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR) MS, stable phase of RRMS and secondary progressive MS (SPMS), on the function of BBB in the presence of fingolimod-phosphate were assessed.
  
  
  RESULTS
  Incubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera.
  
  
  CONCLUSIONS
  Pretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients.
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takeshita
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Koga
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanda
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D002461:Cell Line, Transformed; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D015870:Gene Expression; D006801:Humans; D007106:Immune Sera / Q000009:adverse effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D062507:Claudin-5; D007106:Immune Sera; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011409:Propylene Glycols; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine