Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis

Richard Macrez, Maria C. Ortega, Isabelle Bardou, Anupriya Mehra, Antoine Fournier, Susanne M A Van Der Pol, Benoit Haelewyn, Eric Maubert, Flavie Lesept, Arnaud Chevilley, Fernando De Castro, Helga E. De Vries, Denis Vivien, Diego Clemente, Fabian Docagne*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2406-2419
Number of pages14
JournalBrain
Volume139
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

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