Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis

• Published in: PloS one 2015-03, Vol.10 (3), p.e0121488-e0121488
• Main Authors: Nishihara, Hideaki, Shimizu, Fumitaka, Sano, Yasuteru, Takeshita, Yukio, Maeda, Toshihiko, Abe, Masaaki, Koga, Michiaki, Kanda, Takashi
• Format: Article
• Language: English
• Subjects: Adhesion tests; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - immunology; Blood-Brain Barrier - metabolism; Cell adhesion & migration; Cell Line, Transformed; Central nervous system; Claudin-5 - genetics; Claudin-5 - metabolism; Conditioning; Egress; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Exposure; Fingolimod Hydrochloride; Gene Expression; Humans; Immune Sera - adverse effects; Immune Sera - immunology; Immunoglobulins; Immunosuppressive Agents - pharmacology; Infiltration; Intercellular adhesion molecule 1; Kinases; Lymphocytes; Lymphoid tissue; Maintenance; Medicine; Microvasculature; mRNA; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Nervous system; Neurology; Neurosciences; NF-kappa B - genetics; NF-kappa B - metabolism; NMR; Nuclear magnetic resonance; Patients; Phosphate; Phosphates; Propylene Glycols - pharmacology; Proteins; Receptor mechanisms; Receptors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Tissues; University graduates; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0121488

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. 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. 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. 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.