Cytosolic phospholipase A2 alpha modulates NMDA neurotoxicity in mouse hippocampal cultures

Kenneth Martin Brady, Sarah J. Texel, Koji Kishimoto, Raymond C. Koehler, Adam Sapirstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The arachidonic acid-specific cytosolic phospholipase A2 alpha (cPLA2α) has been implicated in the generation of neurological injuries. cPLA2α-dependent neurological injury has been postulated to be mediated through inflammatory and eicosanoid pathways. We determined if cPLA2α amplifies the injury of a non-inflammatory, excitotoxic stimulus by modifying a well-described toxicity assay to measure the toxicity of N-methyl-d-aspartate (NMDA) in the CA1 region of organotypic, mouse hippocampal cultures. Hippocampal cultures from wild-type and cPLA2α knockout mice were exposed to 5, 7.5 or 10 μm NMDA for 1 h. Toxicity was measured 23 h later. Cultures derived from cPLA 2α-/- mice and cultures treated with the selective inhibitor AACOCF3 were significantly protected from NMDA toxicity, as compared with wild-type cultures. To determine if cPLA2α- dependent toxicity is cyclooxygenase (COX)-2 dependent, COX-2 and PGE 2 levels were measured 7 and 25 h after NMDA treatment. NMDA treatment failed to induce COX-2 protein or increase PGE2 in the culture media in either genotype at either time. In contrast, phorbol 12-myristate 13-acetate and ionophore treatment caused robust induction of COX-2 and PGE2 in both genotypes. We conclude that cPLA2α may have a hitherto unrecognized direct effect on excitatory neurotoxicity, suggesting that cPLA2α inhibition is a therapeutic candidate for treatment of the early, excitotoxic injury observed in stroke.

Original languageEnglish (US)
Pages (from-to)3381-3386
Number of pages6
JournalEuropean Journal of Neuroscience
Volume24
Issue number12
DOIs
StatePublished - Dec 1 2006

Keywords

  • COX-2
  • Excitotoxicity
  • Inhibition
  • NMDA
  • Prostaglandins

ASJC Scopus subject areas

  • Neuroscience(all)

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