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Cyclo-Oxygenase-2 Inhibitors

Rationale and Therapeutic Potential for Alzheimer’s Disease

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Abstract

The newly introduced cyclo-oxygenase-2 (COX-2) inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) have been established as effective agents in treating arthritic conditions, while greatly reducing the gastrointestinal adverse effects of traditional NSAIDs. There are expectations that NSAIDs will be useful in the treatment of Alzheimer’s disease (AD), and that COX-2 inhibitors might have a role. However, a recently reported clinical trial of a COX-2 inhibitor in AD indicated that it was neither protective nor did it accelerate the decline. The expectations were based on pathological evidence of inflammatory changes associated with AD lesions and epidemiological evidence of a reduced prevalence of AD in populations taking NSAIDs. They were supported by preliminary evidence showing efficacy of NSAIDs in treating patients with AD. These data are based on the use of traditional NSAIDs.

Whether COX-2 inhibitors would be similarly effective was uncertain since COX-2 is constitutively expressed in neurons. Animal experiments suggest that COX-2 may be performing adaptive functions associated with normal neurons and protective functions associated with stressed neurons. These results emphasise that the appropriate target for NSAID trials in AD is COX-1, but they also indicate that there would be no contraindication to the use of those traditional NSAIDs which have mixed COX-l/COX-2 inhibiting activity.

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References

  1. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev 1995; 21: 195–218

    Article  PubMed  CAS  Google Scholar 

  2. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiological studies. Neurology 1996; 47: 425–32

    Article  PubMed  CAS  Google Scholar 

  3. Stewart WF, Kawas C, Corrada M, et al. Risk of Alzheimer’s disease and duration of NSAID use. Neurology 1997 March; 48: 626–32

    Article  PubMed  CAS  Google Scholar 

  4. Robitaille A. Improved nonsteroidal anti-inflammatories. Can J Contin Med Educ 1998 July: 85–97

    Google Scholar 

  5. Steering Committee of the Physicians’ Health Study Research Group. Preliminary report: findings from the aspirin component of the ongoing physicians’ health study. N Engl J Med 1988; 318: 262–4

    Article  Google Scholar 

  6. Lane NE. Pain management in osteoarthritis: the role of COX-2 inhibitors. J Rheumatol 1997; 24Suppl. 49: 20–4

    Google Scholar 

  7. Lipsky PE, Isakson PC. Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheumatol 1997; 24Suppl. 49: 9–14

    Google Scholar 

  8. Wilcox CM, Shalek KA, Cotsonsis G. Striking prevalence of over the counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Intern Med 1994; 154(1): 42–6

    Article  PubMed  CAS  Google Scholar 

  9. Mackenzie IRA, Munoz DG. Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology 1998 April; 50: 986–90

    Article  PubMed  CAS  Google Scholar 

  10. Mackenzie IRA. Anti-inflammatory drugs and Alzheimer type pathology in aging. Neurology 2000; 54: 732–4

    Article  PubMed  CAS  Google Scholar 

  11. Beard CM. Kokmen E, Kurland LT. Rheumatoid arthritis and susceptibility to Alzheimer’s disease [letter]. Lancet 1991; 337: 1426

    Article  PubMed  CAS  Google Scholar 

  12. Breitner JCS, Welsh KA, Helms MJ, et al. Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging 1995; 16(4): 523–30

    Article  PubMed  CAS  Google Scholar 

  13. Rich JB, Rasmusson DX, Folstein MF et al. Nonsteroidal antiinflammatory drugs in Alzheimer’s disease. Neurology 1995 Jan; 45: 51–5

    Article  PubMed  CAS  Google Scholar 

  14. Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer’s disease. Neurology 1993 Aug; 43: 1609–11

    Article  PubMed  CAS  Google Scholar 

  15. Scharf S, Mander A, Ugoni A, et al. A double-blind, placebo-controlled trial of diclofenac misoprostol in Alzheimer’s disease. Neurology 1999 Jul; 53(1): 197–201

    Article  PubMed  CAS  Google Scholar 

  16. Sainali SM, Ingram DM, Talwaker S, et al. Results of a double-blind, placebo-controlled study of celecoxib in the treatment of progression of Alzheimer’s disease [abstract]. 6th International Stockholm-Springfield Symposium of Advances in Alzheimer Therapy; 2000 Apr 5–8; Stockholm

  17. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231: 232–5

    PubMed  CAS  Google Scholar 

  18. Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol 1997; 24Suppl. 49: 15–9

    Google Scholar 

  19. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoper-oxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 1996 Dec 27; 271(52): 33157–60

    Article  PubMed  CAS  Google Scholar 

  20. Hawkey CJ. COX-2 inhibitors. Lancet 1999 Jan 23; 353: 307–13

    Article  PubMed  CAS  Google Scholar 

  21. Yasojima K, Schwab C, McGeer EG, et al. Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res 1999; 830: 226–36

    Article  PubMed  CAS  Google Scholar 

  22. Morris JK, Richards JS. An E-box region within the prostaglandin endoperoxide synthase-2 (PGS-2) promoter is required for transcription in rat ovarian granulosa cells. J Biol Chem 1996 July 12; 271(28): 16633–43

    Article  PubMed  CAS  Google Scholar 

  23. Morham SG, Langenbach R, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995 Nov 3; 83: 473–82

    Article  PubMed  CAS  Google Scholar 

  24. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclo-oxygenase II. Nature 1995 Nov 23; 378: 406–9

    Article  PubMed  CAS  Google Scholar 

  25. Langenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995 Nov 3; 83: 483–92

    Article  PubMed  CAS  Google Scholar 

  26. Wallace JL, Chin BC. New generation NSAIDs: the benefits without the risks. Drugs Today 1997 Jul–Aug; 33(6): 371–8

    CAS  Google Scholar 

  27. Schumann P, Touzani O, Young AR, et al. Effects of indomethacin on cerebral blood flow and oxygen metabolism: a positron emission tomographic investigation in the anesthetized baboon. Neurosci Lett 1996; 220: 137–41

    Article  PubMed  Google Scholar 

  28. Reuter BK, Asfaha S, Buret A, et al. Exacerbation of inflammation-associated colonic injury in rats through inhibition of cyclooxygenase-2. J Clin Invest 1996 Nov; 98(9): 2076–85

    Article  PubMed  CAS  Google Scholar 

  29. Kaufmann WE, Andreason KI, Isakson PC, et al. Cyclooxygenases and the central nervous system. Prostaglandins 1997 Sept; 54: 601–24

    PubMed  CAS  Google Scholar 

  30. Kaufmann WE, Worley PF, Pegg J, et al. 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 March; 93: 2317–21

    Article  PubMed  CAS  Google Scholar 

  31. Adams J, Collaco-Moraes Y, de Belleroche J. Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation. J Neurochem 1996; 66(1): 6–13

    Article  PubMed  CAS  Google Scholar 

  32. Yamagata K, Andreasson KI, Kaufmann WE, et al. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 1993 Aug; 11: 371–86

    Article  PubMed  CAS  Google Scholar 

  33. Baik EJ, Kim EJ, Lee SH, et al. Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res 1999; 843: 118–29

    Article  PubMed  CAS  Google Scholar 

  34. Ho L, Osaka H, Aisen PS, et al. Induction of cyclooxygenase (COX)-2 but not COX-1 gene expression in apoptotic cell death. J Neuroimmunol 1998; 89: 142–9

    Article  PubMed  CAS  Google Scholar 

  35. Walton M, Sirimanne E, Williams C, et al. Prostaglandin H synthase-2 and cytosolic phospholipase A(2) in the hypoxic-ischemic brain: role in neuronal survival. Mol Brain Res 1997 Oct 15; 50(1-2): 165–70

    Article  PubMed  CAS  Google Scholar 

  36. Planas AM, Soriano MA, Justicia C, et al. Induction of cyclooxygenase-2 in the rat brain after a mild episode of focal ischemia without tissue inflammation or neural cell damage. Neurosci Lett 1999; 275: 141–4

    Article  PubMed  CAS  Google Scholar 

  37. Nakayama M, Uchimura K, Zhu RL, et al. Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia. Proc Natl Acad Sci USA 1998 Sept 1; 95(18): 10954–9

    Article  PubMed  CAS  Google Scholar 

  38. Nogawa S, Zhang FY, Ross ME, et al. Cyclooxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 1997 Apr 15; 17(8): 2746–55

    PubMed  CAS  Google Scholar 

  39. Hara K, Kong DL, Sharp FR, et al. Effect of selective inhibitors of cyclooxygenase-2 on temporary focal cerebral ischemia in rats. Neurosci Lett 1998; 256: 53–6

    Article  PubMed  CAS  Google Scholar 

  40. Buccellati C, Folco GC, Sala A, et al. Inhibition of prostanoid synthesis protects against neuronal damage induced by focal ischemia in rat brain. Neurosci Lett 1998; 257: 123–6

    Article  PubMed  CAS  Google Scholar 

  41. Inoue H, Yokoyama C, Hara S, et al. Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in endothelial cells. J Biol Chem 1995 Oct 20; 270(42): 24965–71

    Article  PubMed  CAS  Google Scholar 

  42. Lacroix S, Rivest S. Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain. J Neurochem 1998 Feb; 70(2): 452–66

    Article  PubMed  CAS  Google Scholar 

  43. Cao C, Matsumura K, Yamagata K, et al. Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. Brain Res 1996 Sept 16; 733(2): 263–72

    Article  PubMed  CAS  Google Scholar 

  44. Ichitani Y, Shi T, Haeggstrom JZ, et al. Increased levels of cyclooxygenase-2 mRNA in the rat spinal cord after peripheral inflammation: an in situ hybridization study. Neuroreport 1997 Sept 8; 8(13): 2949–52

    Article  PubMed  CAS  Google Scholar 

  45. Chan CC, Boyce S, Brideau C, et al. Rofecoxib [Vioxx, MK-0966; 4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-fura-none]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. J Pharmacol Exp Ther 1999; 290(2): 551–60

    PubMed  CAS  Google Scholar 

  46. Penning TD, Talley JJ, Bertenshaw ST, et al. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-5-(4-methylphe-nyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonam ide (SC-58635, Celecoxib). J Med Chem 1997; 40: 1347–65

    Article  PubMed  CAS  Google Scholar 

  47. Engelhardt G, Bogel R, Schnitzer C, et al. Meloxicam: influence on arachidonic acid metabolism. Biochem Pharmacol 1996; 51: 21–8

    Article  PubMed  CAS  Google Scholar 

  48. Vane JR, Botting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res 1995; 44: 1–10

    Article  PubMed  CAS  Google Scholar 

  49. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclo-oxygenase) iso-enzymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1993 March 25; 268(9): 6610–4

    PubMed  CAS  Google Scholar 

  50. Masferrer JL, Zweifel BS, Manning PT, et al. Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory and nonulcerogenic. Proc Natl Acad Sci U S A 1994 April; 91: 3228–32

    Article  PubMed  CAS  Google Scholar 

  51. Landfield PW, Eldridge JC. Increasing affinity of type II corticosteroid binding in aged rat hippocampus. Exp Neurol 1989; 106: 110–3

    Article  PubMed  CAS  Google Scholar 

  52. Aisen PS, Davis KL, Berg JD, et al. A randomized controlled trial of prednisone in Alzheimer’s disease. Neurology 2000; 54: 588–93

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Our work on Alzheimer disease has been supported by grants from the Alzheimer Societies of British Columbia and Canada, and the Jack Brown and Family A.D. Research Fund, as well as donations from individual British Columbians.

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  1. Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada

    Patrick L. McGeer

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Correspondence to Patrick L. McGeer.

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McGeer, P.L. Cyclo-Oxygenase-2 Inhibitors. Drugs & Aging 17, 1–11 (2000). https://doi.org/10.2165/00002512-200017010-00001

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