The dual role of prostaglandin E2 in excitotoxicity and preconditioning-induced neuroprotection

Tania F. Gendron, Eric Brunette, Joseph S. Tauskela, Paul Morley

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Cyclooxygenase-2 is harmful in models of cerebral ischemia yet plays a protective role in preconditioning-induced ischemic tolerance in the heart. This study examined the mechanisms underlying cyclooxygenase-2-mediated neurotoxicity and preconditioning-induced neuroprotection in an in vitro model of cerebral ischemia. Inhibition of cyclooxygenase-2 protects cortical neuronal cultures from death induced by oxygen-glucose deprivation and reduces oxygen-glucose deprivation-induced increases in intracellular Ca2+ ([Ca2+]i). In the present study, we determined if prostaglandin E2 (PGE2) is responsible for this cyclooxygenase-2-mediated effect. Rat cortical cultures expressed mRNA for the prostanoid EP1-EP4 receptors. PGE2 reversed the attenuation in [Ca2+]i and the protection offered by cyclooxygenase-2 inhibition during oxygen-glucose deprivation. These effects likely occur via activation of the prostanoid EP1 receptor since blocking this receptor during oxygen-glucose deprivation reduced [Ca 2+]i and neurotoxicity. Next, we considered if the moderate activation of this pathway, by preconditioning cultures with sub-lethal oxygen-glucose deprivation, influenced the development of tolerance to an otherwise lethal oxygen-glucose deprivation insult, 48 h later. Inhibition of cyclooxygenase-2 during oxygen-glucose deprivation-preconditioning abolished preconditioning-induced protection. Furthermore, cultures were rendered tolerant to oxygen-glucose deprivation by the transient exposure to exogenous PGE 2 24 h prior to the insult, indicating that this product of the cyclooxygenase-2 pathway is sufficient to induce ischemic tolerance. This study shows that cyclooxygenase-2 and PGE2 are involved in both oxygen-glucose deprivation-induced neurotoxicity and preconditioning-induced neuroprotection. While neurotoxic in the context of lethal oxygen-glucose deprivation, the moderate activation of this signalling pathway confers ischemic tolerance.

Original languageEnglish (US)
Pages (from-to)17-27
Number of pages11
JournalEuropean Journal of Pharmacology
Volume517
Issue number1-2
DOIs
StatePublished - Jul 4 2005

Keywords

  • Ca
  • Cyclooxygenase-2
  • Oxygen-glucose deprivation
  • Preconditioning
  • Primary cortical cultures
  • Prostaglandin E

ASJC Scopus subject areas

  • Pharmacology

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