Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Aid S, Langenbach R, Bosetti F (2008) Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J Neuroinflammation 5:7

    Article  Google Scholar 

  • 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 289:2819–2826

    Article  CAS  Google Scholar 

  • Akundi RS, Candelario-Jalil E, Hess S et al (2005) Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia. Glia 51:199–208

    Article  PubMed  Google Scholar 

  • Allan SM, Rothwell NJ (2003) Inflammation in central nervous system injury. Philos Trans R Soc B Biol Sci 358:1669–1677

    Article  CAS  Google Scholar 

  • Andreasson KI, Savonenko A, Vidensky S et al (2001) Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci 21:8198–8209

    PubMed  CAS  Google Scholar 

  • Bate C, Veerhuis R, Eikelenboom P, Williams A (2003) Neurons treated with cyclo-oxygenase-1 inhibitors are resistant to amyloid-beta1-42. NeuroReport 14:2099–2103

    Article  PubMed  CAS  Google Scholar 

  • 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 95:1563–1574

    Article  PubMed  CAS  Google Scholar 

  • 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 86:545–555

    Article  PubMed  CAS  Google Scholar 

  • Chandrasekharan NV, Simmons DL (2004) The cyclooxygenases. Genome Biol 5:241

    Article  PubMed  CAS  Google Scholar 

  • 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 22:1491–1501

    CAS  Google Scholar 

  • Choi SH, Aid S, Bosetti F (2009) The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci 30:174–181

    Article  PubMed  CAS  Google Scholar 

  • 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):531–541

    Article  PubMed  CAS  Google Scholar 

  • 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 77:85–88

    Article  PubMed  CAS  Google Scholar 

  • 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 162:1220–1231

    Article  PubMed  CAS  Google Scholar 

  • Estrada LD, Soto C (2007) Disrupting beta-amyloid aggregation for Alzheimer disease treatment. Curr Top Med Chem 7:115–126

    Article  PubMed  CAS  Google Scholar 

  • 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 113:113–122

    Article  PubMed  CAS  Google Scholar 

  • Ferrera P, Arias C (2005) Differential effects of COX inhibitors against beta-amyloid-induced neurotoxicity in human neuroblastoma cells. Neurochem Int 47:589–596

    Article  PubMed  CAS  Google Scholar 

  • 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 79:950–958

    Article  PubMed  CAS  Google Scholar 

  • 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 23:963–1008

    Article  CAS  Google Scholar 

  • Heneka MT, O'Banion MK (2007) Inflammatory processes in Alzheimer's disease. J Neuroimmunol 184:69–91

    Article  PubMed  CAS  Google Scholar 

  • Ho L, Luterman JD, Aisen PS, Pasinetti GM, Montine TJ, Morrow JD (2000) Elevated CSF prostaglandin E2 levels in patients with probable AD. Neurology 55:323

    PubMed  CAS  Google Scholar 

  • 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 58:487–492

    Article  PubMed  CAS  Google Scholar 

  • 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 101:2–8

    CAS  Google Scholar 

  • 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 951:218–226

    Article  PubMed  CAS  Google Scholar 

  • 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 61:678–688

    PubMed  CAS  Google Scholar 

  • 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 14:1419–1427

    Article  PubMed  CAS  Google Scholar 

  • Hu J, LaDu MJ, Van Eldik LJ (1998) Apolipoprotein E attenuates beta-amyloid-induced astrocyte activation. J Neurochem 71:1626–1634

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 367:156–159

    Article  PubMed  CAS  Google Scholar 

  • 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 85:1–10

    Article  PubMed  CAS  Google Scholar 

  • 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 93:2317–2321

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 2:355–365

    Article  PubMed  CAS  Google Scholar 

  • Kotilinek LA, Westerman MA, Wang Q et al (2008) Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain 131:651–664

    Article  PubMed  Google Scholar 

  • 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 33:490–499

    Article  PubMed  CAS  Google Scholar 

  • Liang X, Wu L, Wang Q et al (2007) Function of COX-2 and prostaglandins in neurological disease. J Mol Neurosci 33:94–99

    Article  PubMed  CAS  Google Scholar 

  • 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 18:1527–1534

    Article  PubMed  Google Scholar 

  • 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 102:3058–3063

    Article  PubMed  CAS  Google Scholar 

  • 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 12:376–389

    PubMed  CAS  Google Scholar 

  • 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 141:1149–1162

    Article  PubMed  CAS  Google Scholar 

  • Minghetti L (2004) Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 63:901–910

    PubMed  CAS  Google Scholar 

  • Morita I (2002) Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat 68–69:165–175

    Article  PubMed  Google Scholar 

  • Netland EE, Newton JL, Majocha RE, Tate BA (1998) Indomethacin reverses the microglial response to amyloid beta-protein. Neurobiol Aging 19:201–204

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Nivsarkar M, Banerjee A, Padh H (2008) Cyclooxygenase inhibitors: a novel direction for Alzheimer's management. Pharmacol Rep 60:692–698

    PubMed  CAS  Google Scholar 

  • 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 39:804–809

    CAS  Google Scholar 

  • 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 70:1–12

    Article  PubMed  CAS  Google Scholar 

  • Pasinetti GM, Aisen PS (1998) Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain. Neuroscience 87:319–324

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinate, 6th edn. Academic, New York

    Google Scholar 

  • 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 93:1561–1567

    Article  PubMed  CAS  Google Scholar 

  • 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 954:1–10

    Article  PubMed  CAS  Google Scholar 

  • Rogers J, Kirby LC, Hempelman SR et al (1993) Clinical trial of indomethacin in Alzheimer’s disease. Neurology 43:1609–1611

    PubMed  CAS  Google Scholar 

  • 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:e2718

    Article  PubMed  Google Scholar 

  • 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 99:609–614

    Article  CAS  Google Scholar 

  • 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 96:892–899

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    PubMed  CAS  Google Scholar 

  • 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 166:1163–1172

    Article  PubMed  CAS  Google Scholar 

  • Shie FS, Montine KS, Breyer RM, Montine TJ (2005b) Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity. Glia 52:70–77

    Article  PubMed  Google Scholar 

  • Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437

    Article  PubMed  CAS  Google Scholar 

  • Strauss KI (2008) Antiinflammatory and neuroprotective actions of COX2 inhibitors in the injured brain. Brain Behav Immun 22:285–298

    Article  PubMed  CAS  Google Scholar 

  • 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 1088:219–229

    Article  PubMed  CAS  Google Scholar 

  • 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 45:713–719

    Article  PubMed  CAS  Google Scholar 

  • 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 100:5473–5478

    Article  PubMed  CAS  Google Scholar 

  • Ueda K, Fukui Y, Kageyama H (1994) Amyloid beta protein-induced neuronal cell death: neurotoxic properties of aggregated amyloid beta protein. Brain Res 639:240–244

    Article  PubMed  CAS  Google Scholar 

  • 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 63:1410–1424

    Article  PubMed  Google Scholar 

  • Vane JR, Bakhle YS, Botting RM (1998) Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 38:97–120

    Article  PubMed  CAS  Google Scholar 

  • 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 28:536–543

    Article  PubMed  CAS  Google Scholar 

  • 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 1095:85–95

    Article  PubMed  CAS  Google Scholar 

  • Xiang Z, Ho L, Yemul S (2002) Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Expr 10:271–278

    PubMed  CAS  Google Scholar 

  • 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 453:58–61

    Article  PubMed  CAS  Google Scholar 

  • 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 11:371–386

    Article  PubMed  CAS  Google Scholar 

  • Yang H, Chen C (2008) Cyclooxygenase-2 in synaptic signaling. Curr Pharm Des 14:1443–1451

    Article  PubMed  CAS  Google Scholar 

  • 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 830:226–236

    Article  PubMed  CAS  Google Scholar 

  • 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 58:1135–1146

    Article  PubMed  CAS  Google Scholar 

  • 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 803:267–277

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi, Shiva Nasiraei-Moghadam, Azadeh Abdi, Leila Khalaj, Fatemeh Moradi & Abolhassan Ahmadiani

  2. Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi, Azadeh Abdi, Leila Khalaj & Abolhassan Ahmadiani

Authors
  1. Leila Dargahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiva Nasiraei-Moghadam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Azadeh Abdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leila Khalaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fatemeh Moradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Abolhassan Ahmadiani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abolhassan Ahmadiani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dargahi, L., Nasiraei-Moghadam, S., Abdi, A. et al. Cyclooxygenase (COX)-1 Activity Precedes the COX-2 Induction in Aβ-Induced Neuroinflammation. J Mol Neurosci 45, 10–21 (2011). https://doi.org/10.1007/s12031-010-9401-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-010-9401-6

Keywords

Search

Navigation