Kawano T et al. (2006) Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12: 225–229
Cyclo-oxygenase 2 (COX2) inhibitors can be used to protect against neurotoxicity in conditions such as cerebral ischemia and neurodegeneration; however, their long-term use is associated with cardiovascular complications thought to result from blockade of the vasoprotective effects of COX2-derived prostacyclin. Data from a recent study reported in Nature Medicine indicate that inhibition of a downstream effector of COX2—the prostaglandin E2 EP1 receptor—can selectively attenuate hypoxic–ischemic brain lesions without any loss of vasoprotection.
Kawano and colleagues carried out a series of experiments using an animal model of hypoxic–ischemic N-methyl-D-aspartate (NMDA)-induced brain injury. They showed that, following neocortical microinjection of NMDA to mice, administration of an EP1-receptor inhibitor reduced the lesion volume by 31%. Similarly, mice without the gene encoding the EP1 receptor showed a 35% reduction in NMDA lesion volume. In a model of focal cerebral ischemia, administration of an EP1-receptor inhibitor 6 h after transient occlusion of the middle cerebral artery resulted in a 43 ± 10% reduction in infarct volume (P <0.05). Importantly, this protective effect occurred within a therapeutic window similar to that of a COX2 inhibitor. The researchers went on to show that inhibition or inactivation of the EP1 receptor was associated with a preservation of the activity of the Na+–Ca2+ exchanger responsible for enabling neurons to cope with excitotoxicity-associated Ca2+ accumulation.
The authors suggest that pharmacological inhibition of the EP1 receptor might be a viable method of attenuating the detrimental effects of COX2 without impinging on the beneficial activities of this enzyme.
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Kyme, C. Inhibition of a downstream effector of COX2 can attenuate excitotoxic brain injury. Nat Rev Neurol 2, 238 (2006). https://doi.org/10.1038/ncpneuro0166
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DOI: https://doi.org/10.1038/ncpneuro0166