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Role of COX-2 in Inflammatory and Degenerative Brain Diseases

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Inflammation in the Pathogenesis of Chronic Diseases

Part of the book series: Subcellular Biochemistry ((SCBI,volume 42))

In the last decade, the potential role of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) in brain diseases has been extensively studied. COX-2 over-expression has been associated with neurotoxiticy in acute conditions, such as hypoxia/ischemia and seizures, as well as in inflammatory chronic diseases, including Creutzfeldt-Jakob disease (CJD) and Alzheimer’s disease (AD). However, the role played by COX-2 in neurodegenerative diseases is still controversial and further clinical and experimental studies are warranted. In addition, the emerging role of COX-2 in behavioural and cognitive functions strongly indicates that studies aimed at improving our knowledge of the physiological role of COX-2 in the central nervous system are crucial to fully understand the pros and cons of its manipulation in disabling neurological diseases

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References

  • Aisen P.S., Schafer K.A., Grundman M., Pfeiffer E., Sano M., Davis K.L., Farlow M.R., Jin S., ThomasR.G., Thal L.J. Alzheimer’s Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003; 289:2819–2826.

    Article  PubMed  CAS  Google Scholar 

  • Aisen P.S. The potential of anti-inflammatory drugs for the treatment of Alzheimer’s disease. The Lancet Neurology 2002; 1:279–284.

    Article  CAS  Google Scholar 

  • Baker C.A., Lu Z.Y., Zaitsev I., Manuelidis L. Microglial activation varies in different models of Creutzfeldt-Jakob disease. J Virol 1999; 73:5089–5097.

    PubMed  CAS  Google Scholar 

  • Bate C., Rutherford S., Gravenor M., Reid S., Williams A. Cyclo-oxygenase inhibitors protect against prion-induced neurotoxicity in vitro. Neuroreport 2002; 13:1933–1938.

    Article  PubMed  CAS  Google Scholar 

  • Bazan N.G. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res 2003; 44:2221–2233.

    Article  PubMed  CAS  Google Scholar 

  • Betmouni S., Perry V.H., Gordon J.L. Evidence for an early inflammatory response in the central nervous system of mice with scrapie. Neuroscience 1996; 74:1–5.

    Article  PubMed  CAS  Google Scholar 

  • Blais V., Zhang J., Rivest S. In altering the release of glucocorticoids, ketorolac exacerbates the effects of systemic immune stimuli on expression of proinflammatory genes in the brain. Endocrinology. 2002; 143:4820–4827.

    Article  PubMed  CAS  Google Scholar 

  • Blais V., Turrin N.P., Rivest S. Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli. J Neurochem 2005; 95:1563–1574.

    Article  PubMed  CAS  Google Scholar 

  • Bosetti F., Langenbach R., Weerasinghe G.R. Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+-dependent phospholipase A2. J Neurochem 2004; 91:1389–1397.

    Article  PubMed  CAS  Google Scholar 

  • Botting R.M. Mechanism of action of acetaminophen: is there a cyclooxygenase 3? Clin Infect Dis 2000; 31:S202–S210.

    Article  PubMed  CAS  Google Scholar 

  • Breder C.D., Dewitt D., Kraig R.P. Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 1995; 355:296–315.

    Article  PubMed  CAS  Google Scholar 

  • Candelario-Jalil E., Gonzalez-Falcon A., Garcia-Cabrera M., Alvarez D., Al-Dalain S., Martinez G., Leon O.S., Springer J.E. 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 2003; 86:545–555.

    Article  PubMed  CAS  Google Scholar 

  • Chandrasekharan N.V., Dai H., Roos K.L., Evanson N.K., Tomsik J., Elton T.S., Simmons D.L. COX-3, a cycloxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure and expression. Proc. Natl Acad Sci USA 2002; 99:13926–13931.

    Article  PubMed  CAS  Google Scholar 

  • Chang J.W., Coleman P.D., O’Banion M.K. Prostaglandin G/H synthase-2 (cyclooxygenase-2) mRNA expression is decreased in Alzheimer’s disease. Neurobiol Aging 1996; 17:801–808.

    Article  PubMed  CAS  Google Scholar 

  • Chen C., Magee J.C., Bazan N.G. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic activity. J Neurophysiol 2002; 87:2851–2857.

    PubMed  CAS  Google Scholar 

  • Combrinck M., Williams J., De Berardinis M.A., Warden D., Puopolo M., Smith A.D., Minghetti L. Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2006; 77:85–88.

    Article  PubMed  CAS  Google Scholar 

  • De Simone R., Ajmone-Cat M.A., Minghetti L. Atypical antiinflammatory activation of microglia induced by apoptotic neurons: possible role of phosphatidylserine-phosphatidylserine receptor interaction. Mol Neurobiol 2004; 29:197–212.

    Article  PubMed  Google Scholar 

  • Deininger M.H., Bekure-Nemariam K., Trautmann K., Morgalla M., Meyermann R., Schluesener H.J. Cyclooxygenase-1 and -2 in brains of patients who died with sporadic Creutzfeldt-Jakob disease. J Mol Neurosci 2003; 20:25–30.

    Article  PubMed  CAS  Google Scholar 

  • Ek M., Engblom D., Saha S., Blomqvist A., Jakobsson P., Ericsson-Dahlstrand A. Inflammatory response: pathway across the blood-brain barrier. Nature 2001; 410:430–431.

    Article  PubMed  CAS  Google Scholar 

  • Firuzi O., Pratico D. Coxibs and Alzheimer’s disease: should they stay or should they go? Ann Neurol 2006; 59:219–228.

    Article  PubMed  CAS  Google Scholar 

  • Forman M.S., Trojanowski J.Q., Lee V.M. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 2004; 10:1055–1063.

    Article  PubMed  CAS  Google Scholar 

  • Graham S.H., Hickey R.W. Cyclooxygenases in central nervous system diseases: a special role for cyclooxygenase 2 in neuronal cell death. Arch Neurol 2003; 60:628–630.

    Article  PubMed  Google Scholar 

  • Gray F., Chretien F., Adle-Biassette H., Dorandeu A., Ereau T., Delisle M.B., Kopp N., Ironside J.W., Vital C. Neuronal apoptosis in Creutzfeldt-Jakob disease. J Neuropathol Exp Neurol 1999; 58:321–328.

    PubMed  CAS  Google Scholar 

  • Guenther K., Deacon R.M., Perry V.H., Rawlins J.N. Early behavioural changes in scrapie-affected mice and the influence of dapsone. Eur J Neurosci 2001; 14:401–409.

    Article  PubMed  CAS  Google Scholar 

  • Hinz B., Brune K. Cyclooxygenase-2– 10 years later. J Pharm Exp Ther 2002; 300:367–75.

    Article  CAS  Google Scholar 

  • Holscher C. Inhibitors of cyclooxygenase produce amnesia for passive avoidance task in the chick. Eur J Neurosci 1995; 7:1360–1365.

    Article  PubMed  CAS  Google Scholar 

  • Hoozemans J.J., Bruckner M.K., Rozemuller A.J., Veerhuis R., Eikelenboom P., Arendt T. 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 2002; 61:678–688.

    PubMed  CAS  Google Scholar 

  • Hoozemans J.J., Veerhuis R., Rozemuller A.J., Arendt T., Eikelenboom P. Neuronal COX-2 expression and phosphorylation of pRb precede p38 MAPK activation and neurofibrillary changes in AD temporal cortex. Neurobiol Dis 2004; 15:492–499.

    Article  PubMed  CAS  Google Scholar 

  • Hoozemans J.J., van Haastert E.S., Veerhuis R., Arendt T., Scheper W., Eikelenboom P., Rozemuller A.J. Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer’s disease. J Neuroinflammation. 2005; 2:27.

    Article  PubMed  CAS  Google Scholar 

  • in t’ Veld B.A., Ruitenberg A., Hofman A., Launer L.J., van Duijn C.M., Stijnen T., Breteler M.M., Stricker B.H. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001; 345:1515–1521.

    Article  Google Scholar 

  • Kaufmann W.E., Andreasson K.I., Isakson P.C., Worley P.F. Cyclooxygenases and the central nervous system. Prostaglandins 1997; 54:601–624.

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann W.E., Worley P.F., Pegg J., Bremer M., Isakson P. 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 1996; 93:2317–2321.

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann W.E., Worley P.F., Taylor C.V., Bremer M., Isakson P.C. Cyclooxygenase-2 expression during rat neocortical development and in Rett syndrome. Brain Dev 1997; 19:25–34

    Article  PubMed  CAS  Google Scholar 

  • Kis B., Snipes J.A., Busija D.W. Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. J Pharmacol Exp Ther 2005; 315:1–7.

    Article  PubMed  CAS  Google Scholar 

  • Levi G., Minghetti L., Aloisi F. Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie. 1999; 80:899–904.

    Article  Google Scholar 

  • Lukiw W.J., Bazan N.G. Cyclooxygenase 2 RNA message abundance, stability, and hypervariability in sporadic Alzheimer neocortex. J Neurosci Res 1997; 50:937–945.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L., Fritch W., Zaitsev I. Dapsone to delay symptoms in Creutzfeldt-Jakob disease. Lancet 1998; 352:456.

    Article  PubMed  CAS  Google Scholar 

  • McGeer P.L., McGeer E.G. Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging. 2001; 22:799–809.

    Article  PubMed  CAS  Google Scholar 

  • McGeer P.L., Rogers J. Anti-inflammatory agents as a therapeutic approach to Alzheimer’s disease. Neurology. 1992; 42:447–449.

    PubMed  CAS  Google Scholar 

  • Minghetti L., Cardone F., Greco A., Puopolo M., Levi G., Green A.J., Knight R., Pocchiari M. Increased CSF levels of prostaglandin E2 in variant Creutzfeldt-Jakob disease. Neurology 2002; 58:127–129.

    PubMed  CAS  Google Scholar 

  • Minghetti L., Greco A., Cardone F., Puopolo M., Ladogana A., Almonti S., Cunningham C., Perry V.H., Pocchiari M., Levi G. Increased brain synthesis of prostaglandin E2 and F2-isoprostane in human and experimental transmissible spongiform encephalopathies. J Neuropathol Exp Neurol 2000; 59:866–871

    PubMed  CAS  Google Scholar 

  • Minghetti L., Levi G. Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 1998; 54:99–125.

    Article  PubMed  CAS  Google Scholar 

  • Minghetti L., Sbriccoli M., Geloso M.C., Ingrosso L., Di Bari M.A., Greco A., Cardone F., Pocchiari M. Cyclooxygenases and prostaglandin E2 in animal and human prion diseases. Proceedings VII European Meeting on glial cell functions. 2005 May 17–21, Amsterdam. Medimond International Proceeding Publishers,2005.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Montine T.J., Sidell K.R., Crews B.C., Markesbery W.R., Marnett L.J., Roberts L.J. 2nd, Morrow J.D. Elevated CSF prostaglandin E2 levels in patients with probable AD. Neurology 1999; 53:1495–1498.

    PubMed  CAS  Google Scholar 

  • Nagy Z., Esiri M.M., Smith A.D. The cell division cycle and the pathophysiology of Alzheimer’s disease. Neuroscience 1998; 87:731–739.

    Article  PubMed  CAS  Google Scholar 

  • Niwa K., Araki E., Morham S.G., Ross M.E., Iadecola C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci 2000; 20:763–770.

    PubMed  CAS  Google Scholar 

  • O’Neill G.P., Ford-Hutchinson A.W. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett. 1993; 330:156–160.

    Article  PubMed  CAS  Google Scholar 

  • Parente L., Perretti M. Advances in the pathophysiology of constitutive and inducible cyclooxygenases: two enzymes in the spotlight. Biochem Pharmacol 2003; 65:153–159.

    Article  PubMed  CAS  Google Scholar 

  • Pasinetti G.M., Aisen P.S. Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer’s disease brain. Neuroscience 1998; 87:319–324.

    Article  PubMed  CAS  Google Scholar 

  • Pepicelli O., Fedele E., Berardi M., Raiteri M., Levi G., Greco A., Ajmone-Cat M.A., Minghetti L. Cyclo oxygenase-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 2005; 93:1561–1567.

    Article  PubMed  CAS  Google Scholar 

  • Perry V.H., Cunningham C., Boche D. Atypical inflammation in the central nervous system in prion disease. Curr Opin Neurol 2002; 15:349–354.

    Article  PubMed  Google Scholar 

  • Puoti G., Giaccone G., Mangieri M., Limido L., Fociani P., Zerbi P., Suardi S., Rossi G., Iussich S., Capobianco R., Di Fede G., Marcon G., Cotrufo R., Filippini G., Bugiani O., Tagliavini F. Sporadic Creutzfeldt-Jakob disease: the extent of microglia activation is dependent on the biochemical type of PrPSc. J Neuropathol Exp Neurol 2005; 64:902–909.

    PubMed  Google Scholar 

  • Qin N., Zhang S.P., Reitz T.L., Mei J.M., Flores C.M. Cloning, expression, and functional characterization of human cyclooxygenase-1 splicing variants: evidence for intron 1 retention. J Pharmacol Exp Ther. 2005; 315:1298–305.

    Article  PubMed  CAS  Google Scholar 

  • Rall J.M., Mach S.A., Dash P.K. Intrahippocampal infusion of a cyclooxygenase-2 inhibitor attenuates memory acquisition in rats. Brain Res 2003; 968:273–276.

    Article  PubMed  CAS  Google Scholar 

  • Reines S.A., Block G.A., Morris J.C., Liu G., Nessly M.L., Lines C.R., Norman B.A., Baranak C.C. Rofecoxib Protocol 091 Study Group. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology. 2004; 62:66–71.

    PubMed  CAS  Google Scholar 

  • Ricceri L., Minghetti L., Moles A., Popoli P., Confaloni A., De Simone R., Piscopo P., Scattoni M.L., di Luca M., Calamandrei G. Cognitive and neurological deficits induced by early and prolonged basal forebrain cholinergic hypofunction in rats. Exp Neurol. 2004; 189:162–172.

    Article  PubMed  CAS  Google Scholar 

  • Sang N., Zhang J., Marcheselli V., Bazan N.G., Chen C. Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci. 2005; 25:9858–9870.

    Article  PubMed  CAS  Google Scholar 

  • Sharifzadeh M., Naghdi N., Khosrovani S., Ostad S.N., Sharifzadeh K., Roghani A. Post-training intrahippocampal infusion of the COX-2 inhibitor celecoxib impaired spatial memory retention in rats. Eur J Pharmacol. 2005; 511:159–166.

    Article  PubMed  CAS  Google Scholar 

  • Sharifzadeh M., Tavasoli M., Soodi M., Mohammadi-Eraghi S., Ghahremani M.H., Roghani A. A time course analysis of cyclooxygenase-2 suggests a role in spatial memory retrieval in rats. Neurosci Res. 2006; 54:171–179.

    Article  PubMed  CAS  Google Scholar 

  • Schwab J.M., Schluesener H.J. Cyclooxygenases and central nervous system inflammation: conceptual neglect of cyclooxygenase 1. Arch Neurol 2003; 60:630–632.

    Article  PubMed  Google Scholar 

  • Schwieler L., Erhardt S., Nilsson L., Linderholm K., Engberg G. Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons–possible involvement of endogenous kynurenic acid. Synapse. 2006; 59:290–298.

    Article  PubMed  CAS  Google Scholar 

  • Shaftel S.S., Olschowka J.A., Hurley S.D., Moore A.H., O’Banion M.K. COX-3: a splice variant of cyclooxygenase-1 in mouse neural tissue and cells. Brain Res Mol Brain Res 2003; 119:213–215.

    Article  PubMed  CAS  Google Scholar 

  • Shaw K.N., Commins S., O’Mara S.M. Deficits in spatial learning and synaptic plasticity induced by the rapid and competitive broad-spectrum cyclooxygenase inhibitor ibuprofen are reversed by increasing endogenous brain-derived neurotrophic factor. Eur J Neurosci 2003; 17:2438–46.

    Article  PubMed  Google Scholar 

  • Simard A.R., Rivest S. Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer’s disease. Mol Psychiatry 2006; 11:327–335.

    Article  PubMed  CAS  Google Scholar 

  • Sternberg E.M. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol. 2006; 6:318–328.

    Article  PubMed  CAS  Google Scholar 

  • Streit W.J. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia. 2002; 40:133–139.

    Article  PubMed  Google Scholar 

  • Teather L.A., Packard M.G., Bazan N.G. Post-training cyclooxygenase-2 (COX-2) inhibition impairs memory consolidation. Learn Mem 2002; 9:41–47.

    Article  PubMed  Google Scholar 

  • Vazquez-Tello A., Fan L., Hou X., Joyal J.S., Mancini J.A., Quiniou C., Clyman R.I., Gobeil F.Jr, Varma D.R., Chemtob S. Intracellular-specific colocalization of prostaglandin E2 synthases and cyclooxygenases in the brain. Am J Physiol Regul Integr Comp Physiol. 2004; 287:R1155–R1163.

    PubMed  CAS  Google Scholar 

  • Walsh D.T., Perry V.H., Minghetti L. Cyclooxygenase-2 is highly expressed in microglial-like cells in a murine model of prion disease. Glia 2000; 29:392–396

    Article  PubMed  CAS  Google Scholar 

  • Webber K.M., Raina A.K., Marlatt M.W., Zhu X., Prat M.I., Morelli L., Casadesus G., Perry G., Smith M.A. The cell cycle in Alzheimer disease: a unique target for neuropharmacology. Mech Ageing Dev. 2005; 126:1019–1025.

    Article  PubMed  CAS  Google Scholar 

  • Will R.G., Alperovitch A., Poser S., Pocchiari M., Hofman A., Mitrova E., de Silva R., D’Alessandro M. Delasnerie-Laupretre N., Zerr I., van Duijn C. Descriptive epidemiology of Creutzfeldt-Jakob disease in six European countries, 1993–1995. EU Collaborative Study Group for CJD. Ann Neurol. 1998; 43:763–767.

    Article  PubMed  CAS  Google Scholar 

  • Will R.G., Ironside J.W., Zeidler M., Cousens S.N., Estibeiro K., Alperovitch A., Poser S., Pocchiari M, Hofman A., Smith P.G. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347:921–925

    Article  PubMed  CAS  Google Scholar 

  • Yamagata K., Andreasson K.I., Kaufmann W.E., Barnes C.A., Worley P.F. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 1993; 11:371–386.

    Article  PubMed  CAS  Google Scholar 

  • Yasojima K., Schwab C., McGeer E.G., McGeer P.L. Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res 1999; 830:226–236.

    Article  PubMed  CAS  Google Scholar 

  • Yermakova A.V., O’Banion M.K. Downregulation of neuronal cyclooxygenase-2 expression in end stage Alzheimer’s disease. Neurobiol Aging 2001; 22:823–836.

    Article  PubMed  CAS  Google Scholar 

  • Yermakova A.V., Rollins J., Callahan L.M., Rogers J., O’Banion M.K. Cyclooxygenase-1 in human Alzheimer’s, and control brain: quantitative analysis of expression by microglia and CA3 hippocampal neurons. J Neuropathol Exp Neurol 1999; 58:1135–1146.

    Article  PubMed  CAS  Google Scholar 

  • Zhang J., Rivest S. Anti-inflammatory effects of prostaglandin E2 in the central nervous system in response to brain injury and circulating lipopolysaccharide. J Neurochem 2001; 76:855–64.

    Article  PubMed  CAS  Google Scholar 

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Minghetti, L. (2007). Role of COX-2 in Inflammatory and Degenerative Brain Diseases. In: Harris, R.E., et al. Inflammation in the Pathogenesis of Chronic Diseases. Subcellular Biochemistry, vol 42. Springer, Dordrecht. https://doi.org/10.1007/1-4020-5688-5_5

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