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Journal of Molecular Neuroscience

, Volume 45, Issue 1, pp 10–21 | Cite as

Cyclooxygenase (COX)-1 Activity Precedes the COX-2 Induction in Aβ-Induced Neuroinflammation

  • Leila Dargahi
  • Shiva Nasiraei-Moghadam
  • Azadeh Abdi
  • Leila Khalaj
  • Fatemeh Moradi
  • Abolhassan AhmadianiEmail author
Article

Abstract

Two different isoforms of cyclooxygenases, COX-1 and COX-2, are constitutively expressed under normal physiological conditions of the central nervous system, and accumulating data indicate that both isoforms may be involved in different pathological conditions. However, the distinct role of COX-1 and COX-2 and the probable interaction between them in neuroinflammatory conditions associated with Alzheimer’s disease are conflicting issues. The aim of this study was to elucidate the comparable role of each COX isoform in neuroinflammatory response induced by β-amyloid peptide (Aβ). Using histological and biochemical methods, 13 days after stereotaxic injection of Aβ into the rat prefrontal cortex, hippocampal neuroinflammation and neuronal injury were confirmed by increased expression of tumor necrosis factor-alpha (TNF-α) and COX-2, elevated levels of prostaglandin E2 (PGE2), astrogliosis, activation of caspase-3, and neuronal cell loss. Selective COX-1 or COX-2 inhibitors, SC560 and NS398, respectively, were chronically used to explore the role of COX-1 and COX-2. Treatment with either COX-1 or COX-2 selective inhibitor or their combination equally decreased the level of TNF-α, PGE2, and cleaved caspase-3 and attenuated astrogliosis and neuronal cell loss. Interestingly, treatment with COX-1 selective inhibitor or the combined COX inhibitors prevented the induction of COX-2. These results indicate that the activity of both isoforms is detrimental in neuroinflammatory conditions associated with Aβ, but COX-1 activity is necessary for COX-2 induction and COX-2 activity seems to be the main source of PGE2 increment.

Keywords

β-Amyloid peptide Neuroinflammation Cyclooxygenase-1 Cyclooxygenase-2 Prostaglandin E2 

Notes

Acknowledgments

The authors are grateful to T. Al-Tarihi, M. Motevalian, and F. Khodagholi for their valuable help and to Neuroscience Research Center of Shahid Beheshti University of Medical Sciences for financial support.

References

  1. Aid S, Langenbach R, Bosetti F (2008) Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J Neuroinflammation 5:7CrossRefGoogle Scholar
  2. Aisen PS, Schafer KA, Grundman M et al (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. J Am Med Assoc 289:2819–2826CrossRefGoogle Scholar
  3. Akundi RS, Candelario-Jalil E, Hess S et al (2005) Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia. Glia 51:199–208PubMedCrossRefGoogle Scholar
  4. Allan SM, Rothwell NJ (2003) Inflammation in central nervous system injury. Philos Trans R Soc B Biol Sci 358:1669–1677CrossRefGoogle Scholar
  5. Andreasson KI, Savonenko A, Vidensky S et al (2001) Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci 21:8198–8209PubMedGoogle Scholar
  6. Bate C, Veerhuis R, Eikelenboom P, Williams A (2003) Neurons treated with cyclo-oxygenase-1 inhibitors are resistant to amyloid-beta1-42. NeuroReport 14:2099–2103PubMedCrossRefGoogle Scholar
  7. Blais V, Turrin NP, Rivest S (2005) Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli. J Neurochem 95:1563–1574PubMedCrossRefGoogle Scholar
  8. Candelario-Jalil E, Gonzalez-Falcon A, Garcia-Cabrera M et al (2003) Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia induced oxidative damage and neurodegeneration following transient global cerebral ischemia. J Neurochem 86:545–555PubMedCrossRefGoogle Scholar
  9. Chandrasekharan NV, Simmons DL (2004) The cyclooxygenases. Genome Biol 5:241PubMedCrossRefGoogle Scholar
  10. Choi SH, Langenbach R, Bosetti F (2008) Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury. J Fed Am Soc Exp Biol 22:1491–1501Google Scholar
  11. Choi SH, Aid S, Bosetti F (2009) The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci 30:174–181PubMedCrossRefGoogle Scholar
  12. Chung DW, Yoo KY, Hwang IK et al (2010) Systemic administration of lipopolysaccharide induces cyclooxygenase-2 immunoreactivity in endothelium and increases microglia in the mouse hippocampus. Cell Mol Neurobiol 30(4):531–541PubMedCrossRefGoogle Scholar
  13. Combrinck M, Williams J, De Berardinis MA et al (2006) Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer's disease. J Neurol Neurosurg Psychiatry 77:85–88PubMedCrossRefGoogle Scholar
  14. Echeverria V, Burgess S, Gamble-George J et al (2009) Sorafenib inhibits nuclear factor kappa B, decreases inducible nitric oxide synthase and cyclooxygenase-2 expression, and restores working memory in APPswe mice. Neuroscience 162:1220–1231PubMedCrossRefGoogle Scholar
  15. Estrada LD, Soto C (2007) Disrupting beta-amyloid aggregation for Alzheimer disease treatment. Curr Top Med Chem 7:115–126PubMedCrossRefGoogle Scholar
  16. Fehrenbacher JC, Burkey TH, Nicol GD, Vasko MR (2005) Tumor necrosis factor alpha and interleukin-1beta stimulate the expression of cyclooxygenase II but do not alter prostaglandin E2 receptor mRNA levels in cultured dorsal root ganglia cells. Pain 113:113–122PubMedCrossRefGoogle Scholar
  17. Ferrera P, Arias C (2005) Differential effects of COX inhibitors against beta-amyloid-induced neurotoxicity in human neuroblastoma cells. Neurochem Int 47:589–596PubMedCrossRefGoogle Scholar
  18. Fiebich BL, Schleicher S, Spleiss O, Czygan M, Hull M (2001) Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes: possible involvement of EP4-like receptors, p38 mitogen activated protein kinase and protein kinase C. J Neurochem 79:950–958PubMedCrossRefGoogle Scholar
  19. Harkany T, Hortobagyi T, Sasvari M et al (1999) Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity: relevance to Alzheimer’s disease. Prog Neuro Psychopharmacol Biol Psychiatry 23:963–1008CrossRefGoogle Scholar
  20. Heneka MT, O'Banion MK (2007) Inflammatory processes in Alzheimer's disease. J Neuroimmunol 184:69–91PubMedCrossRefGoogle Scholar
  21. Ho L, Luterman JD, Aisen PS, Pasinetti GM, Montine TJ, Morrow JD (2000) Elevated CSF prostaglandin E2 levels in patients with probable AD. Neurology 55:323PubMedGoogle Scholar
  22. Ho L, Purohit D, Haroutunian V et al (2001) Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease. Arch Neurol 58:487–492PubMedCrossRefGoogle Scholar
  23. Hoozemans JJ, Rozemuller AJ, Janssen I, de Groot CJ, Veerhuis R, Eikelenboom P (2001) Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain. Acta Neuropathologica Berl 101:2–8Google Scholar
  24. Hoozemans JJ, Veerhuis R, Janssen I, van Elk EJ, Rozemuller AJ, Eikelenboom P (2002a) The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer's disease. Brain Res 951:218–226PubMedCrossRefGoogle Scholar
  25. Hoozemans JJ, Brückner MK, Rozemuller AJ, Veerhuis R, Eikelenboom P, Arendt T (2002b) 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 61:678–688PubMedGoogle Scholar
  26. Hoozemans JJ, Rozemuller JM, van Haastert ES, Veerhuis R, Eikelenboom P (2008) Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology. Curr Pharm Des 14:1419–1427PubMedCrossRefGoogle Scholar
  27. Hu J, LaDu MJ, Van Eldik LJ (1998) Apolipoprotein E attenuates beta-amyloid-induced astrocyte activation. J Neurochem 71:1626–1634PubMedCrossRefGoogle Scholar
  28. Im JY, Kim D, Paik SG, Han PL (2006) Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. Free Radic Biol Med 41:960–972PubMedCrossRefGoogle Scholar
  29. Iwata R, Kitagawa K, Zhang NY, Wu B, Inagaki C (2004) Non-steroidal anti-inflammatory drugs protect amyloid beta protein-induced increase in the intracellular Cl concentration in cultured rat hippocampal neurons. Neurosci Lett 367:156–159PubMedCrossRefGoogle Scholar
  30. Jeohn GH, Kong LY, Wilson B, Hudson P, Hong JS (1998) Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures. J Neuroimmunol 85:1–10PubMedCrossRefGoogle Scholar
  31. Kaufmann WE, Worley PF, 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. Proc Natl Acad Sci U S A 93:2317–2321PubMedCrossRefGoogle Scholar
  32. Kawano T, Anrather J, Zhou P et al (2006) Prostaglandin E-2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12:225–229PubMedCrossRefGoogle Scholar
  33. Klegeris A, McGeer PL (2005) Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Curr Alzheimer Res 2:355–365PubMedCrossRefGoogle Scholar
  34. Kotilinek LA, Westerman MA, Wang Q et al (2008) Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain 131:651–664PubMedCrossRefGoogle Scholar
  35. Li W, Wu S, Hickey RW, Rose ME, Chen J, Graham SH (2008) Neuronal cyclooxygenase-2 activity and prostaglandins PGE2, PGD2, and PGF2 alpha exacerbate hypoxic neuronal injury in neuron-enriched primary culture. Neurochem Res 33:490–499PubMedCrossRefGoogle Scholar
  36. Liang X, Wu L, Wang Q et al (2007) Function of COX-2 and prostaglandins in neurological disease. J Mol Neurosci 33:94–99PubMedCrossRefGoogle Scholar
  37. Maihofner C, Probst-Cousin S, Bergmann M, Neuhuber W, Neundorfer B, Heuss D (2003) Expression and localization of cyclooxygenase-1 and -2 in human sporadic amyotrophic lateral sclerosis. Eur J Neurosci 18:1527–1534PubMedCrossRefGoogle Scholar
  38. Malinin NL, Wright S, Seubert P, Schenk D, Griswold-Prenner I (2005) Amyloid-beta neurotoxicity is mediated by FISH adapter protein and ADAM12 metalloprotease activity. Proc Natl Acad Sci U S A 102:3058–3063PubMedCrossRefGoogle Scholar
  39. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) Beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12:376–389PubMedGoogle Scholar
  40. Melnikova T, Savonenko A, Wang Q et al (2006) Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern. Neuroscience 141:1149–1162PubMedCrossRefGoogle Scholar
  41. Minghetti L (2004) Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 63:901–910PubMedGoogle Scholar
  42. Morita I (2002) Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat 68–69:165–175PubMedCrossRefGoogle Scholar
  43. Netland EE, Newton JL, Majocha RE, Tate BA (1998) Indomethacin reverses the microglial response to amyloid beta-protein. Neurobiol Aging 19:201–204PubMedCrossRefGoogle Scholar
  44. Nicol GD, Klingberg DK, Vasko MR (1992) Prostaglandin E2 increases calcium conductance and stimulates release of substance P in avian sensory neurons. J Neurosci 12:1917–1927PubMedGoogle Scholar
  45. Nivsarkar M, Banerjee A, Padh H (2008) Cyclooxygenase inhibitors: a novel direction for Alzheimer's management. Pharmacol Rep 60:692–698PubMedGoogle Scholar
  46. Pan XD, Chen XC, Zhu YG, Chen LM, Zhang J (2008) Effect of inflammatory responses in microglia induced by oligomeric β-amyloid1–42 on neuronal cells. Acta Anatomica Sinica 39:804–809Google Scholar
  47. Paris D, Townsend KP, Obregon DF, Humphrey J, Mullan M (2002) Pro-inflammatory effect of freshly solubilized beta-amyloid peptides in the brain. Prostaglandins Other Lipid Mediat 70:1–12PubMedCrossRefGoogle Scholar
  48. Pasinetti GM, Aisen PS (1998) Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain. Neuroscience 87:319–324PubMedCrossRefGoogle Scholar
  49. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinate, 6th edn. Academic, New YorkGoogle Scholar
  50. Pepicelli O, Fedel E, Berardi M et al (2005) Cyclooxygenase-1 and -2 differently contribute to prostaglandin E2 synthesis and lipid peroxidation after in vivo activation of N-methyl-D-aspartate receptors in rat hippocampus. J Neurochem 93:1561–1567PubMedCrossRefGoogle Scholar
  51. Richardson RL, Kim E, Shephar RA, Gardiner T, Cleary J, O’Hare E (2002) Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated Abeta (1–42) injections in the rat. Brain Res 954:1–10PubMedCrossRefGoogle Scholar
  52. Rogers J, Kirby LC, Hempelman SR et al (1993) Clinical trial of indomethacin in Alzheimer’s disease. Neurology 43:1609–1611PubMedGoogle Scholar
  53. Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L (2008) Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS ONE 3:e2718PubMedCrossRefGoogle Scholar
  54. Schwab JM, Nguyen TD, Postler E, Meyermann R, Schluesener HJ (2000) Selective accumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia. Acta Neuropathologica Berl 99:609–614CrossRefGoogle Scholar
  55. Schwab JM, Beschorner R, Meyermann R, Gozalan F, Schluesener HJ (2002) Persistent accumulation ofcyclooxygenase-1-expressing microglial cells and macrophages and transient upregulation by endothelium in human brain injury. J Neurosurg 96:892–899PubMedCrossRefGoogle Scholar
  56. Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741–766PubMedGoogle Scholar
  57. Shie FS, Breyer RM, Montine TJ (2005a) Microglia lacking E prostanoid receptor subtype 2 have enhanced abeta phagocytosis yet lack abeta-activated neurotoxicity. Am J Pathol 166:1163–1172PubMedCrossRefGoogle Scholar
  58. Shie FS, Montine KS, Breyer RM, Montine TJ (2005b) Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity. Glia 52:70–77PubMedCrossRefGoogle Scholar
  59. Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437PubMedCrossRefGoogle Scholar
  60. Strauss KI (2008) Antiinflammatory and neuroprotective actions of COX2 inhibitors in the injured brain. Brain Behav Immun 22:285–298PubMedCrossRefGoogle Scholar
  61. Suzumura A, Takeuchi H, Zhang G, Kuno R, Mizuno T (2006) Roles of glia-derived cytokines on neuronal degeneration and regeneration. Ann N Y Acad Sci 1088:219–229PubMedCrossRefGoogle Scholar
  62. Takadera T, Shiraishi Y, Ohyashiki T (2004) Prostaglandin E2 induced caspase-dependent apoptosis possibly through activation of EP2 receptors in cultured hippocampal neurons. Neurochem Int 45:713–719PubMedCrossRefGoogle Scholar
  63. Teismann P, Tieu K, Choi DK et al (2003) Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proc Natl Acad Sci U S A 100:5473–5478PubMedCrossRefGoogle Scholar
  64. Ueda K, Fukui Y, Kageyama H (1994) Amyloid beta protein-induced neuronal cell death: neurotoxic properties of aggregated amyloid beta protein. Brain Res 639:240–244PubMedCrossRefGoogle Scholar
  65. Van der Stelt M, Mazzola C, Esposito G et al (2006) Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels. Cell Mol Life Sci 63:1410–1424PubMedCrossRefGoogle Scholar
  66. Vane JR, Bakhle YS, Botting RM (1998) Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 38:97–120PubMedCrossRefGoogle Scholar
  67. Weggen S, Rogers M, Eriksen J (2007) NSAIDs: small molecules for prevention of Alzheimer's disease or precursors for future drug development? Trends Pharmacol Sci 28:536–543PubMedCrossRefGoogle Scholar
  68. Xia Y, Yamagata K, Krukoff TL (2006) Differential expression of the CD14/TLR4 complex and inflammatory signaling molecules following i.c.v. administration of LPS. Brain Res 1095:85–95PubMedCrossRefGoogle Scholar
  69. Xiang Z, Ho L, Yemul S (2002) Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Expr 10:271–278PubMedGoogle Scholar
  70. Xu J, Wang S, Lin Y, Cao L, Wang R, Chi Z (2009) Ghrelin protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett 453:58–61PubMedCrossRefGoogle Scholar
  71. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11:371–386PubMedCrossRefGoogle Scholar
  72. Yang H, Chen C (2008) Cyclooxygenase-2 in synaptic signaling. Curr Pharm Des 14:1443–1451PubMedCrossRefGoogle Scholar
  73. Yasojima K, Schwab C, McGeer EG, McGeer PL (1999) Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res 830:226–236PubMedCrossRefGoogle Scholar
  74. Yermakova AV, Rollins J, Callahan LM, Rogers J, O'Banion MK (1999) Cyclooxygenase-1 in human Alzheimer and control brain: quantitative analysis of expression by microglia and CA3 hippocampal neurons. J Neuropathol Exp Neurol 58:1135–1146PubMedCrossRefGoogle Scholar
  75. Yue H, Strauss KI, Borenstein MR, Barbe MF, Rossi LJ, Jansen SA (2004) Determination of bioactive eicosanoids in brain tissue by a sensitive reversed-phase liquid chromatographic method with fluorescence detection. J Chromatogr B Anal Technol Biomed Life Sci 803:267–277CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Leila Dargahi
    • 1
    • 2
  • Shiva Nasiraei-Moghadam
    • 1
  • Azadeh Abdi
    • 1
    • 2
  • Leila Khalaj
    • 1
    • 2
  • Fatemeh Moradi
    • 1
  • Abolhassan Ahmadiani
    • 1
    • 2
    Email author
  1. 1.Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Department of PharmacologySchool of Medicine, Shahid Beheshti University of Medical SciencesTehranIran

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