Laquinimod enhances central nervous system barrier functions

• Published in: Neurobiology of disease 2017-06, Vol.102, p.60-69
• Main Authors: Lühder, Fred, Kebir, Hania, Odoardi, Francesca, Litke, Tanja, Sonneck, Maike, Alvarez, Jorge Ivan, Winchenbach, Jan, Eckert, Nadine, Hayardeny, Liat, Sorani, Ella, Lodygin, Dmitri, Flügel, Alexander, Prat, Alexandre
• Format: Article
• Language: English
• Subjects: Adult; Animals; Blood brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Capillary Permeability - drug effects; Capillary Permeability - physiology; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - metabolism; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Experimental autoimmune encephalomyelitis; Female; Human brain endothelial cells; Humans; Laquinimod; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - metabolism; Neurology; Neuroprotective Agents - pharmacology; Oral MS therapy; Quinolones - pharmacology; Rats, Inbred Lew; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Young Adult
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2017.02.002

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 TH 1 and TH 17 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.