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Journal of Molecular Neuroscience

, Volume 33, Issue 1, pp 94–99 | Cite as

Function of COX-2 and Prostaglandins in Neurological Disease

  • X. Liang
  • L. Wu
  • Q. Wang
  • T. Hand
  • M. Bilak
  • L. McCullough
  • K. Andreasson
Article

Abstract

Induction of COX-2 expression and enzymatic activity promotes neuronal injury in a number of models of neurological disease. Inhibition of COX-2 activity, either genetically or pharmacologically, has been shown to be neuroprotective in rodent models of stroke, Parkinson’s disease, and amyotrophic lateral sclerosis. Inhibition of COX activity with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces inflammation and amyloid accumulation in murine transgenic models of Familial Alzheimer’s disease, and the use of NSAIDs decreases the risk of developing Alzheimer’s disease in healthy aging populations. COX-mediated neuronal injury is presumed be due to downstream effects of one or more prostaglandin products including PGE2, PGD2, PGF, PGI2 (prostacylin) and TXA2 (thromboxane) that effect cellular changes through activation of specific prostaglandin receptor subtypes and second messenger systems. In this proceeding, we review recent data demonstrating effects of prostaglandin signaling on neuronal viability that are paradoxically protective, when taken in the context that COX-2 induces neuronal injury in the setting of excitotoxicity. Conversely, in the context of an inflammatory stimulus, the EP2 receptor enhances neuronal injury. These findings argue for an additional level of complexity in the prostaglandin response in neurological disease.

Keywords

Cyclooxygenase-2 (COX-2) Prostaglandins Neurological disease 

Notes

Acknowledgements

This work was supported by the American Federation for Aging Research Beeson Award (KA), the American Heart Association (LM), AG15799 (KA), CDMRP PR043148 (KA), NS045727 (KA), and the MDA (KA).

References

  1. Abe, H., Takeshita, T., Nagata, K., Arita, T., Endo, Y., Fujita, T., et al. (1999). Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family. Gene, 227, 71–77.PubMedCrossRefGoogle Scholar
  2. Adams, J., Collaco-Moraes, Y., & de Belleroche, J. (1996). Cyclooxygenase-2 induction in cerebral cortex: An intracellular response to synaptic excitation. Journal of Neurochemistry, 66, 6–13.PubMedCrossRefGoogle Scholar
  3. Akaike, A., Kaneko, S., Tamura, Y., Nakata, N., Shiomi, H., Ushikubi, F., et al. (1994). Prostaglandin E2 protects cultured cortical neurons against N-methyl-d-aspartate receptor-mediated glutamate cytotoxicity. Brain Research, 663, 237–244.PubMedCrossRefGoogle Scholar
  4. Andreasson, K. I., Savonenko, A., Vidensky, S., Goellner, J. J., Zhang, Y., Shaffer, A., et al. (2001). Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. Journal of Neuroscience, 21, 8198–8209.PubMedGoogle Scholar
  5. Bensimon, G., Lacomblez, L., & Meininger, V. (1994). A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. New England Journal of Medicine, 330, 585–591.PubMedCrossRefGoogle Scholar
  6. Bilak, M., Wu L., Wang, Q., Haughey, N., Conant, K., St Hillaire, C., et al. (2004). PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis. Annals of Neurology, 56, 240–248.PubMedCrossRefGoogle Scholar
  7. Breder, C. D., Dewitt, D., & Kraig, R. P. (1995). Characterization of inducible cyclooxygenase in rat brain. Journal of Comparative Neurology, 355, 296–315.PubMedCrossRefGoogle Scholar
  8. Breyer, R. M., Bagdassarian, C. K., Myers, S. A., & Breyer, M. D. (2001). Prostanoid receptors: subtypes and signaling. Annual Review of Pharmacology and Toxicology, 41, 661–690.PubMedCrossRefGoogle Scholar
  9. Carlson, N. G. (2003). Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2 inhibitor APHS can be reversed by a prostanoid. Journal of Neuroscience Research, 71, 71–88.CrossRefGoogle Scholar
  10. Cazevielle, C., Muller, A., Meynier, F., Dutrait, N., & Bonne, C. (1994). Protection by prostaglandins from glutamate toxicity in cortical neurons. Neurochemistry International, 24, 156–159.Google Scholar
  11. Chen, C., Magee, J. C., & Bazan, N. G. (2002). Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. Journal of Neurophysiology, 87, 2851–2857.PubMedGoogle Scholar
  12. Dore, S., Otsuka, T., Mito, T., Sugo, N., Hand, T., Wu, L., et al. (2003). Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction. Annals of Neurology, 54, 155–162.PubMedCrossRefGoogle Scholar
  13. Drachman, D. B., Frank, K., Dykes-Hoberg, M., Teismann, P., Almer, G., Przedborski, S., et al. (2002). Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Annals of Neurology, 52, 771–778.PubMedCrossRefGoogle Scholar
  14. Feng, Z. H., Wang, T. G., Li, D. D., Fung, P., Wilson, B. C., Liu, B., et al. (2002). Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neuroscience Letters, 329, 354–358.PubMedCrossRefGoogle Scholar
  15. Govoni, S., Masoero, E., Favalli, L., Rozza, A., Scelsi, R., Viappiani, S., et al. (2001). The cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat. Neuroscience Letters, 303, 91–94.PubMedCrossRefGoogle Scholar
  16. Hata, A. N., Zent, R., Breyer, M. D., & Breyer, R. M. (2003). Expression and molecular pharmacology of the mouse CRTH2 receptor. Journal of Pharmacology and Experimental Therapeutics, 306, 463–470.PubMedCrossRefGoogle Scholar
  17. Hirai, H., Tanaka, K., Yoshie, O., Ogawa, K., Kenmotsu, K., Takamori, Y., et al (2001). Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. Journal of Experimental Medicine, 193, 255–261.PubMedCrossRefGoogle Scholar
  18. Hirata, M., Kakizuka, A., Aizawa, M., Ushikubi, F., & Narumiya, S. (1994). Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene. Proceedings of the National Academy of Sciences of the United States of America, 91, 11192–11196.PubMedCrossRefGoogle Scholar
  19. Kaufmann, W. E., Andreasson, K. I., Isakson, P. C., & Worley, P. F. (1997). Cyclooxygenases and the central nervous system. Prostaglandins, 54, 601–624.PubMedCrossRefGoogle Scholar
  20. Kaufmann, W. E., Worley, P. F., Pegg, J., Bremer, M., & Isakson, P. (1996). Cox-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 93, 2317–2321.PubMedCrossRefGoogle Scholar
  21. Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P., & Meininger, B. for the Amyotrophic Lateral Sclerosis Study Group II (1996). Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet, 347, 1425–1431.PubMedGoogle Scholar
  22. Liang, X., Wang, Q., Hand, T., Wu, L., Breyer, R. M., Montine, T. J., et al. (2005a). Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer’s disease. Journal of Neuroscience, 25, 10180–10187.PubMedCrossRefGoogle Scholar
  23. Liang, X. B., Wu, L. J., Hand, T., & Andreasson, K. (2005b). PGD2 mediates a neuroprotective effect via the DP1 receptor. Journal of Neurochemistry, 92, 477–485.PubMedCrossRefGoogle Scholar
  24. Liu, D., Wu, L., Breyer, R., Mattson, M. P., & Andreasson, K. (2005). Neuroprotection mediated by the PGE2 EP2 receptor in permanent focal cerebral ischemia. Annals of Neurology, 57, 758–761.PubMedCrossRefGoogle Scholar
  25. McCullough, L., Wu, L., Haughey, N., Liang, X., Hand, T., Wang, Q., et al. (2004). Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. Journal of Neuroscience, 24, 257–268.PubMedCrossRefGoogle Scholar
  26. Miettinen, S., Fusco, F. R., Yrjanheikki, J., Keinanen, R., Hirvonen, T., Roivainen, R., et al. (1997). Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-d-aspartic acid-receptors and phospholipase A2. Proceedings of the National Academy of Sciences of the United States of America, 94, 6500–6505.PubMedCrossRefGoogle Scholar
  27. Monneret, G., Gravel, S., Diamond, M., Rokach, J., & Powell, W. S. (2001). Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor. Blood, 98, 1942–1948.PubMedCrossRefGoogle Scholar
  28. Montine, T. J., Milatovic, D., Gupta, R. C., Valyi-Nagy, T., Morrow, J. D., & Breyer, R. M. (2002). Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. Journal of Neurochemistry, 83, 463–470.PubMedCrossRefGoogle Scholar
  29. Nakayama, M., Uchimura, K., Zhu, R. L., Nagayama, T., Rose, M. E., Stetler, R. A., et al. (1998). Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia. Proceedings of the National Academy of Sciences of the United States of America, 95, 10954–10959.PubMedCrossRefGoogle Scholar
  30. Nogawa, S., Zhang, F., Ross, M. E., & Iadecola, C. (1997). Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. Journal of Neuroscience, 17, 2746–2755.PubMedGoogle Scholar
  31. Pompl, P. N., Ho, L., Bianchi, M., McManus, T., Qin, W., & Pasinetti, G. M. (2003). A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB Journal, 10, 1096.Google Scholar
  32. Prasad, K. N., La Rosa, F. G., & Prasad, J. E. (1998). Prostaglandins act as neurotoxin for differentiated neuroblastoma cells in culture and increase levels of ubiquitin and beta-amyloid. In Vitro Cellular and Developmental Biology, Animal, 34, 265–274.CrossRefGoogle Scholar
  33. Rothstein, J. D., Jin, L., Dykes-Hoberg, M., & Kuncl, R. W. (1993). Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 90, 6591–6595.PubMedCrossRefGoogle Scholar
  34. Rothstein, J. D., Martin, L. J., & Kuncl, R. W. (1992). Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. New England Journal of Medicine, 326, 1464–1468.PubMedCrossRefGoogle Scholar
  35. Rothstein, J. D., Tsai, G., Kuncl, R. W., Clawson, L., Cornblath, D. R., Drachman, D. B., et al. (1990). Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Annals of Neurology, 28, 18–25.PubMedCrossRefGoogle Scholar
  36. Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J., & Kuncl, R. W. (1995). Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Annals of Neurology, 38, 73–84.PubMedCrossRefGoogle Scholar
  37. Smith, W. L., Marnett, L. J., & DeWitt, D. L. (1991). Prostaglandin and thromboxane biosynthesis. Pharmacology and Therapeutics, 48, 153–179.CrossRefGoogle Scholar
  38. Takadera, T., Yumoto, H., Tozuka, Y., & Ohyashiki, T. (2002). Prostaglandin E2 induces caspase-dependent apoptosis in rat cortical cells. Neuroscience Letters, 317, 61–64.PubMedCrossRefGoogle Scholar
  39. Teismann, P., Tieu, K., Choi, D. K., Wu, D. C., Naini, A., Hunot, S., et al. (2003). Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America, 100, 5473–5478.PubMedCrossRefGoogle Scholar
  40. Wu, L., Wang, Q., Lians, X., & Andreasson, K. (2007). Divergent effects of prostaglandin receptor signaling on neuronal survival. Neuroscience Letters, 421, 253–258.PubMedCrossRefGoogle Scholar
  41. Yamagata, K., Andreasson, K., Kaufmann, W. E., Barnes, C. A., & Worley, P. F. (1993). Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron, 11, 371–386.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • X. Liang
    • 1
    • 4
  • L. Wu
    • 1
  • Q. Wang
    • 1
    • 4
  • T. Hand
    • 1
  • M. Bilak
    • 1
  • L. McCullough
    • 3
  • K. Andreasson
    • 1
    • 2
    • 4
  1. 1.Department of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of NeurologyUniversity of Connecticut Health CenterFarmingtonUSA
  4. 4.Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA

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