title: N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis.
abstract: Optic neuritis is a common clinical manifestation of the chronic inflammatory CNS disease multiple sclerosis that can result in persistent visual impairment caused by degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs). Using a model of experimental autoimmune encephalomyelitis with optic neuritis (Brown Norway rats), we show that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists memantine or MK801 results in RGC protection, axon protection, and reduced demyelination of optic nerves. Calcium imaging revealed that RGC responses to glutamate stimulation predominantly occurred via NMDA receptors and were inhibited by memantine in a dose-dependent manner. In contrast, oligodendrocytes were mainly responsive through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor. This suggests that NMDA receptor blockade protected RGCs directly and that the protection was independent of effects on oligodendrocytes. Moreover, increased RGC survival was observed before the onset of optic nerve demyelination--when RGC degeneration had already started. These results indicate an important pathophysiologic role for NMDA receptor-mediated glutamate toxicity during the induction phase of this disease model and highlight a potential target for therapeutic neuroprotection in human optic neuritis.
authors.affiliation: From the Department of Neurology, Hannover Medical School, Hannover (K-WS); Department of Neuro-oncology, University Clinic Heidelberg, Heidelberg (RF, SKW, RD), Germany; and Departments of Neurology (KH) and Pharmacology and Toxicology (AC), University of the Saarland, Homburg/Saar.
authors.forename: Kurt-Wolfram
authors.initials: KW
authors.lastname: Sühs
authors.forename: Richard
authors.initials: R
authors.lastname: Fairless
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Williams
authors.forename: Katrin
authors.initials: K
authors.lastname: Heine
authors.forename: Adolfo
authors.initials: A
authors.lastname: Cavalié
authors.forename: Ricarda
authors.initials: R
authors.lastname: Diem
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D005260:Female; D008559:Memantine / Q000627:therapeutic use*; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009444:Neuritis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology; D009902:Optic Neuritis / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013266:Stilbamidines
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D013266:Stilbamidines; D016291:Dizocilpine Maleate; D002118:Calcium; D008559:Memantine