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Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity

Nature Medicine volume 12, pages 225–229 (2006)Cite this article

Abstract

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has been implicated in the neurotoxicity resulting from hypoxia-ischemia, and its inhibition has therapeutic potential for ischemic stroke. However, COX-2 inhibitors increase the risk of cardiovascular complications. We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E2 EP1 receptors are essential for the neurotoxicity mediated by COX-2–derived prostaglandin E2. EP1 receptors disrupt Ca2+ homeostasis by impairing Na+-Ca2+ exchange, a key mechanism by which neurons cope with excess Ca2+ accumulation after an excitotoxic insult. Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca2+ dysregulation underlying excitotoxic neuronal death. Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion. An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke.

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Figure 1: EP1 receptors contribute to excitotoxic and ischemic brain injury.
Figure 2: EP1 receptors mediate COX-2 neurotoxicity.
Figure 3: EP1 receptors contribute to NMDA-induced [Ca2+]i dysregulation.
Figure 4: EP1 receptors contribute to the impairment of Na+-Ca2+ exchange induced by NMDA.

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Acknowledgements

Supported by US National Institutes of Health (NIH) grants NS35806 and NS34179. C.I. is the recipient of a Javits award from NIH/National Institute of Neurological Disorders and Stroke. We thank B.H. Koller and S.L. Tilley for providing the Ep1−/− mice, L. Qian for studies in hippocampal slice cultures, C. Gooden for tissue cultures studies and C. Pardee for assistance with histology.

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  1. Takayuki Kawano and Josef Anrather: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Neurobiology, Department of Neurology and Neuroscience, 411 East 69th St., Weill Medical College of Cornell University, New York, 10021, New York, USA

    Takayuki Kawano, Josef Anrather, Ping Zhou, Laibaik Park, Gang Wang, Kelly A Frys, Alexander Kunz, Sunghee Cho, Marcello Orio & Costantino Iadecola

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Correspondence to Costantino Iadecola.

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Supplementary information

Supplementary Fig. 1

SC51089 is neuroprotective without influencing physiological parameters. (PDF 520 kb)

Supplementary Fig. 2

SC51089 reduces the hippocampal damage produced byoxygen-glucose deprivation but not microglial activation. (PDF 737 kb)

Supplementary Fig. 3

EP1 receptors are present in neurons. (PDF 9892 kb)

Supplementary Fig. 4

NMDA receptors, EP1 receptors, COX-2, and PGE2 synthase are present in neuronal cultures. (PDF 6158 kb)

Supplementary Fig. 5

Effect of SC51089 on the [Ca++]i elevation elicited by glutamate and on Ca++ currents. (PDF 735 kb)

Supplementary Methods

Methods for assessment of neurological deficits. (PDF 72 kb)

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Kawano, T., Anrather, J., Zhou, P. et al. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12, 225–229 (2006). https://doi.org/10.1038/nm1362

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