title: Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis.
abstract: Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Richard
authors.initials: R
authors.lastname: Macrez
authors.affiliation: 4 Grupo de Grupo de Neurobiología del Desarrollo-GNDe. Hospital Nacional de Parapléjicos - Toledo, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ortega
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bardou
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Mehra
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Fournier
authors.affiliation: 5 Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: Van der Pol
authors.affiliation: 6 Centre Universitaire de Ressources Biologiques, Université de Caen Basse-Normandie, Caen, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Haelewyn
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Eric
authors.initials: E
authors.lastname: Maubert
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Lesept
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevilley
authors.affiliation: 4 Grupo de Grupo de Neurobiología del Desarrollo-GNDe. Hospital Nacional de Parapléjicos - Toledo, Spain 7 Grupo de Neurobiología del Desarrollo-GNDe. Instituto Cajal. CSIC - Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: de Castro
authors.affiliation: 5 Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: De Vries
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.affiliation: 4 Grupo de Grupo de Neurobiología del Desarrollo-GNDe. Hospital Nacional de Parapléjicos - Toledo, Spain 8 Grupo de Neuroimmuno-reparación. Hospital Nacional de Parapléjicos - Toledo, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Clemente
authors.affiliation: 1 INSERM, INSERM-U919, Caen Cedex, F-14074 France 2 Universite' de Caen BasseNormandie, Caen Cedex, F-14074 France 3 GIP Cyceron, Caen, F-14074 France docagne@cyceron.fr.
authors.forename: Fabian
authors.initials: F
authors.lastname: Docagne
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D042783:Endothelial Cells; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D010959:Tissue Plasminogen Activator
keywords: Glunomab; N-methyl-D-aspartate receptors; multiple sclerosis; neuroinflammation; tissue plasminogen activator