ERK1 plays a critical protective role against N-methyl-D-aspartate-induced retinal injury

Toru Nakazawa, Masahiko Shimura, Morin Ryu, Kohji Nishida, Gilles Pagès, Jacques Pouysségur, Shogo Endo

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)136-144
Number of pages9
JournalJournal of Neuroscience Research
Volume86
Issue number1
DOIs
Publication statusPublished - 2008 Jan

Keywords

  • Excitatory amino acids
  • Glia
  • Protein kinase
  • Retinal ganglion cell death
  • Signal transduction

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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