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Neuronal Cyclooxygenase-2 Activity and Prostaglandins PGE2, PGD2, and PGF2α Exacerbate Hypoxic Neuronal Injury in Neuron-enriched Primary Culture

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Abstract

Cyclooxygenase-2 (COX-2) activity has been implicated in the pathogenesis of cerebral ischemia. To determine whether COX-2 activity within the neuron itself exacerbates hypoxic neuronal injury, neuron-enriched cultures were subjected to anoxia. Treatment with COX-2 selective antagonists decreased cell death. Neurons cultured from homozygous COX-2 gene disrupted mice were resistant to hypoxia compared to those of heterozygotes. Infection of primary neurons with AAV expressing COX-2 exacerbated cell death compared to neurons infected with enhanced green fluorescent protein (EGFP) control vector. Addition of PGE2, PGD2 or PGF2α to the medium exacerbated injury, suggesting that the deleterious effects of COX-2 overexpression in hypoxia could be mediated by direct receptor mediated effects of prostaglandins. Overexpression of COX-2 did not increase expression of cyclin D1 or phosphoretinoblastoma protein (pRb), or cleavage of caspase 3 suggesting that this cell cycle mechanism does not mediate COX-2 toxicity in this model.

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References

  1. Nakayama M, Uchimura K, Zhu RL et al (1998) Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia. Proc Natl Acad Sci USA 95:10954–10959

    Article  PubMed  CAS  Google Scholar 

  2. Nogawa S, Zhang F, Ross E et al (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 14:2746–2755

    Google Scholar 

  3. Iadecola C, Niwa K, Nogawa S et al (2001) Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci USA 98:1294–1299

    Article  PubMed  CAS  Google Scholar 

  4. Yamagata K, Andreasson KI, Kaufmann WE et al (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11:371–386

    Article  PubMed  CAS  Google Scholar 

  5. Kaufmann WE, Worley PF, Pegg J et al (1996) COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 93:2317–2321

    Article  PubMed  CAS  Google Scholar 

  6. Hewett SJ, Uliasz TF, Vidwans AS et al (2000) Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. J Pharmacol Exp Ther 293:417–425

    PubMed  CAS  Google Scholar 

  7. Strauss KI, Marini AM (2002) Cyclooxygenase-2 inhibition protects cultured cerebellar granule neurons from glutamate-mediated cell death. J Neurotrauma 19:627–638

    Article  PubMed  Google Scholar 

  8. Huang Y, Liu J, Wang LZ et al (2005) Neuroprotective effects of cyclooxygenase-2 inhibitor celecoxib against toxicity of LPS-stimulated macrophages toward motor neurons. Acta Pharmacol Sin 26:952–958

    Article  PubMed  CAS  Google Scholar 

  9. Maslinska D, Wozniak R, Kaliszek A et al (1999) Expression of cyclooxygenase-2 in astrocytes of human brain after global ischemia. Folia Neuropathol 37:75–79

    PubMed  CAS  Google Scholar 

  10. Tomimoto H, Akiguchi I, Wakita H et al (2000) Cyclooxygenase-2 is induced in microglia during chronic cerebral ischemia in humans. Acta Neuropathol (Berl) 99:26–30

    Article  CAS  Google Scholar 

  11. Vijitruth R, Liu M, Choi DY et al (2006) Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson’s disease. J Neuroinflammation 3:6

    Article  PubMed  Google Scholar 

  12. Wiman KG (1993) The retinoblastoma gene: role in cell cycle control and cell differentiation. Faseb J 7:841–845

    PubMed  CAS  Google Scholar 

  13. Padmanabhan J, Park DS, Greene LA et al (1999) Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J Neurosci 19:8747–8756

    PubMed  CAS  Google Scholar 

  14. Osuga H, Osuga S, Wang F et al (2000) Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci USA 97:10254–10259

    Article  PubMed  CAS  Google Scholar 

  15. Hoozemans JJ, Bruckner MK, Rozemuller AJ et al (2002) Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex. J Neuropathol Exp Neurol 61:678–688

    PubMed  CAS  Google Scholar 

  16. Nicol GD, Klingberg DK, Vasko MR (1992) Prostaglandin E2 increases calcium conductance and stimulates release of substance P in avian sensory neurons. J Neurosci 12:1917–1927

    PubMed  CAS  Google Scholar 

  17. Watabe A, Sugimoto Y, Honda A et al (1993) Cloning and expression of cDNA for a mouse EP1 subtype of prostaglandin E receptor. J Biol Chem 268:20175–20178

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Im JY, Kim D, Paik SG et al (2006) Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. Free Radic Biol Med 41:960–972

    Article  PubMed  CAS  Google Scholar 

  20. Whalen JD, Thomson AW, Lu L et al (2001) Viral IL-10 gene transfer inhibits DTH responses to soluble antigens: evidence for involvement of genetically modified dendritic cells and macrophages. Mol Ther 4:543–550

    Article  PubMed  CAS  Google Scholar 

  21. Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic—ischemic brain damage. Ann Neurol 19:105–111

    Article  PubMed  CAS  Google Scholar 

  22. Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379

    PubMed  CAS  Google Scholar 

  23. Benveniste H, Drejer J, Schousboe A et al (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374

    Article  PubMed  CAS  Google Scholar 

  24. Lauritzen M, Hansen AJ (1992) The effect of glutamate receptor blockade on anoxic depolarization and cortical spreading depression. J Cereb Blood Flow Metab 12:223–229

    PubMed  CAS  Google Scholar 

  25. Iadecola C, Forster C, Nogawa S et al (1999) Cyclooxygenase-2 immunoreactivity in the human brain following cerebral ischemia. Acta Neuropathol (Berl) 98:9–14

    Article  CAS  Google Scholar 

  26. Nogawa S, Zhang F, Ross ME et al (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 17:2746–2755

    PubMed  CAS  Google Scholar 

  27. Bazan N Jr (1970) Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain. Biochim Biophys Acta 218:1–10

    PubMed  CAS  Google Scholar 

  28. Abe K, Kogure K, Yamamoto H et al (1987) Mechanism of arachidonic acid liberation during ischemia in gerbil cerebral cortex. J Neurochem 48:503–509

    Article  PubMed  CAS  Google Scholar 

  29. Katsura K, Rodriguez de Turco EB, Folbergrova J et al (1993) Coupling among energy failure, loss of ion homeostasis, and phospholipase A2 and C activation during ischemia. J Neurochem 61:1677–1684

    Article  PubMed  CAS  Google Scholar 

  30. Bonventre JV, Huang Z, Taheri MR et al (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390:622–625

    Article  PubMed  CAS  Google Scholar 

  31. Miettinen S, Fusco FR, Yrjanheikki J 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. Proc Natl Acad Sci USA 94:6500–6505

    Article  PubMed  CAS  Google Scholar 

  32. Carlson NG (2003) Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2 inhibitor APHS can be reversed by a prostanoid. J Neurosci Res 71:79–88

    Article  PubMed  CAS  Google Scholar 

  33. Goldberg MP, Weiss JH, Pham PC et al (1987) N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture. J Pharmacol Exp Ther 243:784–791

    PubMed  CAS  Google Scholar 

  34. Kaku DA, Giffard RG, Choi DW (1993) Neuroprotective effects of glutamate antagonists and extracellular acidity. Science 260:1516–1518

    Article  PubMed  CAS  Google Scholar 

  35. Asanuma M, Nishibayashi-Asanuma S, Miyazaki I et al (2001) Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals. J Neurochem 76:1895–1904

    Article  PubMed  CAS  Google Scholar 

  36. Lleo A, Berezovska O, Herl L et al (2004) Nonsteroidal anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation. Nat Med 10:1065–1066

    Article  PubMed  CAS  Google Scholar 

  37. Tegeder I, Pfeilschifter J, Geisslinger G (2001) Cyclooxygenase-independent actions of cyclooxygenase inhibitors. Faseb J 15:2057–2072

    Article  PubMed  CAS  Google Scholar 

  38. Drachman DB, Frank K, Dykes-Hoberg M et al (2002) Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann Neurol 52:771–778

    Article  PubMed  CAS  Google Scholar 

  39. Scali C, Prosperi C, Vannucchi MG et al (2000) Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer’s disease. Eur J Neurosci 12:1900–1912

    Article  PubMed  CAS  Google Scholar 

  40. Carrasco E, Casper D, Werner P (2005) Dopaminergic neurotoxicity by 6-OHDA and MPP+: differential requirement for neuronal cyclooxygenase activity. J Neurosci Res 81:121–131

    Article  PubMed  CAS  Google Scholar 

  41. Araki E, Forster C, Dubinsky JM et al (2001) Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke 32:2370–2375

    Article  PubMed  CAS  Google Scholar 

  42. DuBois RN, Shao J, Tsujii M et al (1996) G1 delay in cells overexpressing prostaglandin endoperoxide synthase-2. Cancer Res 56:733–737

    PubMed  CAS  Google Scholar 

  43. Pasinetti GM (2002) Cyclooxygenase as a target for the antiamyloidogenic activities of nonsteroidal anti-inflammatory drugs in Alzheimer’s disease. Neurosignals 11:293–297

    Article  PubMed  CAS  Google Scholar 

  44. Wu Chen R, Zhang Y, Rose ME et al (2004) Cyclooxygenase-2 activity contributes to neuronal expression of cyclin D1 after anoxia/ischemia in vitro and in vivo. Brain Res Mol Brain Res 132:31–37

    Article  PubMed  Google Scholar 

  45. Honda A, Sugimoto Y, Namba T et al (1993) Cloning and expression of a cDNA for mouse prostaglandin E receptor EP2 subtype. J Biol Chem 268:7759–7762

    PubMed  CAS  Google Scholar 

  46. Funk CD, Furci L, FitzGerald GA et al (1993) Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype. J Biol Chem 268:26767–26772

    PubMed  CAS  Google Scholar 

  47. Ahmad M, Saleem S, Zhuang H et al (2006) 1-hydroxyPGE reduces infarction volume in mouse transient cerebral ischemia. Eur J Neurosci 23:35–42

    Article  PubMed  Google Scholar 

  48. Boie Y, Rushmore TH, Darmon-Goodwin A et al (1994) Cloning and expression of a cDNA for the human prostanoid IP receptor. J Biol Chem 269:12173–12178

    PubMed  CAS  Google Scholar 

  49. Abramovitz M, Boie Y, Nguyen T et al (1994) Cloning and expression of a cDNA for the human prostanoid FP receptor. J Biol Chem 269:2632–2636

    PubMed  CAS  Google Scholar 

  50. Toh H, Ichikawa A, Narumiya S (1995) Molecular evolution of receptors for eicosanoids. FEBS Lett 361:17–21

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by National Institutes of Health, National Institute of Neurological Diseases and Stroke Grant No R01-NS37459 (SHG), the VA Merit Review Program (SHG) and the National Institutes of Health, National Institute of Child Health and Human Development Grant No. KO8-HD40848 (RWH), and the Competitive Medical Research Fund of the University of Pittsburgh Medical Center Health System (RWH).

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Authors and Affiliations

  1. Geriatric Research Educational and Clinical Center (00-GR-H), V.A. Pittsburgh Healthcare System, Highland Drive, Pittsburgh, PA, 15205, USA

    Wen** Li, Shasha Wu, Marie E. Rose, Jun Chen & Steven H. Graham

  2. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Wen** Li, Shasha Wu, Marie E. Rose, Jun Chen & Steven H. Graham

  3. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Robert W. Hickey

  4. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jun Chen

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  1. Wen** Li
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  2. Shasha Wu
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Correspondence to Steven H. Graham.

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Li, W., Wu, S., Hickey, R.W. et al. Neuronal Cyclooxygenase-2 Activity and Prostaglandins PGE2, PGD2, and PGF2α Exacerbate Hypoxic Neuronal Injury in Neuron-enriched Primary Culture. Neurochem Res 33, 490–499 (2008). https://doi.org/10.1007/s11064-007-9462-2

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  • DOI: https://doi.org/10.1007/s11064-007-9462-2

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