Microsomal prostaglandin E synthase-1 and cyclooxygenase-2 are both required for ischaemic excitotoxicity

Br J Pharmacol. 2010 Mar;159(5):1174-86. doi: 10.1111/j.1476-5381.2009.00595.x. Epub 2010 Jan 29.


Background and purpose: Although both microsomal prostaglandin E synthase (mPGES)-1 and cyclooxygenase (COX)-2 are critical factors in stroke injury, but the interactions between these enzymes in the ischaemic brain is still obscure. This study examines the hypothesis that mPGES-1 activity is required for COX-2 to cause neuronal damage in ischaemic injury.

Experimental approach: We used a glutamate-induced excitotoxicity model in cultures of rat or mouse hippocampal slices and a mouse middle cerebral artery occlusion-reperfusion model in vivo. The effect of a COX-2 inhibitor on neuronal damage in mPGES-1 knockout (KO) mice was compared with that in wild-type (WT) mice.

Key results: In rat hippocampal slices, glutamate-induced excitotoxicity, as well as prostaglandin (PG) E(2) production and PGES activation, was significantly attenuated by either MK-886 or NS-398, inhibitors of mPGES-1 and COX-2 respectively; however, co-application of these inhibitors had neither an additive nor a synergistic effect. The protective effect of NS-398 on the excitotoxicity observed in WT slices was completely abolished in mPGES-1 KO slices, which showed less excitotoxicity than WT slices. In the transient focal ischaemia model, mPGES-1 and COX-2 were co-localized in the infarct region of the cortex. Injection of NS-398 reduced not only ischaemic PGE(2) production, but also ischaemic injuries in WT mice, but not in mPGES-1 KO mice, which showed less dysfunction than WT mice.

Conclusion and implications: Microsomal prostaglandin E synthase-1 and COX-2 are co-induced by excess glutamate in ischaemic brain. These enzymes are co-localized and act together to exacerbate stroke injury, by excessive PGE(2) production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / enzymology
  • Brain Ischemia / physiopathology*
  • Cyclooxygenase 2 / drug effects
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Female
  • Glutamic Acid / metabolism
  • Hippocampus / metabolism
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsomes / metabolism
  • Neurons / drug effects
  • Neurons / pathology
  • Prostaglandin-E Synthases
  • Rats
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / physiopathology*
  • Stroke / enzymology
  • Stroke / physiopathology


  • Cyclooxygenase 2 Inhibitors
  • Glutamic Acid
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Dinoprostone