title: ERK1 plays a critical protective role against N-methyl-D-aspartate-induced retinal injury.
abstract: Excitotoxicity has been implicated in several ischemic diseases of the retina, including retinal vessel occlusion and diabetic retinopathy. Glutamate signaling mediated through the N-methyl-D-aspartate (NMDA) receptor contributes to ischemic cell death. The NMDA receptor antagonists MK-801 and memantine have substantial neuroprotective effects in experimental retinal disease models, but the mechanisms by which NMDA receptor activity leads to cell death is not clear. Here we describe a previously unknown role for retinal glial cells in NMDA-induced retinal injury that involves the activation of ERK1/2. Within 1 hr after injecting NMDA intravitreally, activation of ERK1/2 and c-Fos induction were observed in retinal Müller cells. The roles of activated ERK1/2 in neuronal damage were examined using ERK1 gene deficient mice (homozygous ERK1(-/-) mice). NMDA-induced ERK1/2 activation in retina was significantly suppressed in ERK1(-/-) mice, and these mice had significantly higher numbers of TUNEL-positive retinal cells than wild-type mice 24 hr after NMDA injection. These data suggest that, during NMDA injury, Müller cells are activated and play a protective role against NMDA-induced retinal cell death. ERK1 appears to play a major role in this process. These new findings on retinal glial cell response during NMDA injury offer an important new therapeutic target for preventing many retinal disorders associated with excitotoxicity.
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan. ntoru@oph.med.tohoku.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shimura
authors.forename: Morin
authors.initials: M
authors.lastname: Ryu
authors.forename: Kohji
authors.initials: K
authors.lastname: Nishida
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000172:deficiency / Q000502:physiology*; D016202:N-Methylaspartate / Q000633:toxicity*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012164:Retinal Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; D016202:N-Methylaspartate; D048052:Mitogen-Activated Protein Kinase 3; D005974:Glutamate-Ammonia Ligase