Prostaglandin EP1 receptor contributes to excitotoxicity and focal ischemic brain damage

Abdullah Shafique Ahmad, Sofiyan Saleem, Muzamil Ahmad, Sylvain Doré

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

The clinical side effects associated with the inhibition of cyclooxygenase enzymes under pathologic conditions have recently raised concerns. A better understanding of neuroinflammatory mechanisms and neuronal survival requires knowledge of cyclooxygenase downstream pathways, especially PGE2 and its G-protein-coupled receptors. In this study, we postulate that EP1 receptor is one of the mechanisms that propagate neurotoxicity and could be a therapeutic target in brain injury. This hypothesis was tested by pretreating C57BL/ 6 wildtype mice with the EP1 receptor selective agonist ONO-DI-004 and the selective antagonist ONO-8713, followed by striatal unilateral NMDA injection. Results revealed that ONO-DI-004 increased NMDA-induced lesion volume up to 128.7 ± 12.0%, while ONO-8713 significantly decreased lesion volume to 71.3 ± 10.9%, as compared to the NMDA-control group. Neurotoxic EP1 receptor properties were also studied using C57BL/6 EP1 receptor knockout (EP1-/-) mice, which revealed a significant decrease to 74.5 ± 8.2%, as compared to wildtype controls. The protective effect of the antagonist ONO-8713 was also tested in the EP1-/- mice, revealing no additional protection in these mice. Together, these results support the selectivity of ONO-8713 toward EP1 receptor and suggest the neurotoxic role of EP1 receptor. Furthermore, the EP1 receptor role in ischemic brain damage was investigated using a model of middle cerebral artery occlusion (MCAO) and reperfusion. The infarct volume was significantly reduced to 56.9 ± 11.5% in EP1-/- mice, as compared to wildtype controls. This is the first study that demonstrates that EP1 receptor aggravates neurotoxicity and that modulation of this receptor can determine the outcomes in both excitotoxic and focal ischemic neuronal damage.

Original languageEnglish (US)
Pages (from-to)265-270
Number of pages6
JournalToxicological Sciences
Volume89
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Keywords

  • Cerebral ischemia
  • Cyclooxygenase
  • Neurotoxicity
  • PGE
  • Stroke

ASJC Scopus subject areas

  • Toxicology

Fingerprint

Dive into the research topics of 'Prostaglandin EP1 receptor contributes to excitotoxicity and focal ischemic brain damage'. Together they form a unique fingerprint.

Cite this