Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis
| Autor: | María Cristina Ortega, Richard Macrez, Fabian Docagne, Fernando de Castro, Antoine P. Fournier, Benoit Haelewyn, Flavie Lesept, Isabelle Bardou, Susanne M. A. van der Pol, Diego Clemente, Helga E. de Vries, Eric Maubert, Denis Vivien, Anupriya Mehra, Arnaud Chevilley |
|---|---|
| Přispěvatelé: | Molecular cell biology and Immunology, Amsterdam Neuroscience - Neuroinfection & -inflammation |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Encephalomyelitis Autoimmune Experimental Nerve Tissue Proteins Biology Pharmacology Blood–brain barrier Tissue plasminogen activator Receptors N-Methyl-D-Aspartate 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Humans Receptor Neuroinflammation Mice Knockout Multiple sclerosis Experimental autoimmune encephalomyelitis Glutamate receptor Endothelial Cells medicine.disease Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure HEK293 Cells Blood-Brain Barrier Tissue Plasminogen Activator Immunology NMDA receptor Neurology (clinical) Excitatory Amino Acid Antagonists 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Macrez, R, Ortega, M C, Bardou, I, Mehra, A, Fournier, A, Van Der Pol, S M A, Haelewyn, B, Maubert, E, Lesept, F, Chevilley, A, De Castro, F, De Vries, H E, Vivien, D, Clemente, D & Docagne, F 2016, ' Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis ', Brain, vol. 139, no. 9, pp. 2406-2419 . https://doi.org/10.1093/brain/aww172 Brain, 139(9), 2406-2419. Oxford University Press |
| ISSN: | 0006-8950 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|