title: Laquinimod enhances central nervous system barrier functions.
abstract: Laquinimod is currently being tested as a therapeutic drug in multiple sclerosis. However, its exact mechanism of action is still under investigation. Tracking of fluorescently-tagged encephalitogenic T cells during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, revealed that laquinimod significantly reduces the invasion of pathogenic effector T cells into the CNS tissue. T-cell activation, differentiation and amplification within secondary lymphoid organs after immunization with myelin antigen, their migratory capacity and re-activation within the nervous tissue were either only mildly affected or remained unchanged. Instead, laquinimod directly impacted the functionality of the CNS vasculature. The expression of tight junction proteins p120 and ZO-1 in human brain endothelial cells was up-regulated upon laquinimod treatment, resulting in a significant increase in the transendothelial electrical resistance of confluent monolayers of brain endothelial cells. Similarly, expression of the adhesion molecule activated leukocyte cell adhesion molecule (ALCAM) and inflammatory chemokines CCL2 and IP-10 was suppressed, leading to a significant reduction in the migration of memory TH1 and TH17 lymphocytes across the blood brain barrier (BBB). Our data indicate that laquinimod exerts its therapeutic effects by tightening the BBB and limiting parenchymal invasion of effector T cells, thereby reducing CNS damage.
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany.
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.affiliation: Neuroimmunology Research Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Médecine, Université de Montréal, Montreal, Quebec H2L 4M1, Canada.
authors.forename: Hania
authors.initials: H
authors.lastname: Kebir
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Odoardi
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Litke
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Sonneck
authors.affiliation: Neuroimmunology Research Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Médecine, Université de Montréal, Montreal, Quebec H2L 4M1, Canada.
authors.forename: Jorge Ivan
authors.initials: JI
authors.lastname: Alvarez
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Winchenbach
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Eckert
authors.affiliation: Teva Pharmaceutical Industries Ltd., 5 Bazel Street, Petah Tiqva 49131, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.affiliation: Teva Pharmaceutical Industries Ltd., 5 Bazel Street, Petah Tiqva 49131, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Sorani
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Lodygin
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Centre Goettingen, Göttingen D-37075, Germany; Max-Planck-Institute for Experimental Medicine, Göttingen D-37075, Germany. Electronic address: Fluegel@med.uni-goettingen.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Flügel
authors.affiliation: Neuroimmunology Research Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Médecine, Université de Montréal, Montreal, Quebec H2L 4M1, Canada; Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada. Electronic address: a.prat@umontreal.ca.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
mesh_terms: D000328:Adult; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
chemical_list: D018696:Neuroprotective Agents; D015363:Quinolones; C476223:laquinimod
keywords: Blood brain barrier; Experimental autoimmune encephalomyelitis; Human brain endothelial cells; Laquinimod; Oral MS therapy