Skip to main content

Advertisement

Log in

Anti-inflammatory agents in Alzheimer’s disease

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Epidemiologic studies have raised expectations that existing anti-inflammatory drugs may be useful in slowing the progression of Alzheimer’s disease (AD). However, the first large-scale studies of anti-inflammatory drug treatment regimens have been negative. These disappointing results, along with new evidence from cell culture and animal model systems, suggest that the inflammatory hypothesis must be refined. Generalizations about inflammation and anti-inflammatory drugs have not been useful in developing treatment strategies for AD. But new studies suggest that specific anti-inflammatory drugs may have beneficial effects mediated by unexpected mechanisms. Continued exploration of the neuroprotective potential of specific antirheumatic therapies, as well as consideration of treatment duration and subject selection, will improve the outlook for successful development of one or more of these drugs in the prevention or treatment of AD.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Campbell IL, Abraham CR, Masliah E, et al.: Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 1993, 90:10061–10065.

    Article  PubMed  CAS  Google Scholar 

  2. Fagarasan MO, Aisen PS: Il-1 and anti-inflammatory drugs modulate AΒ cytotoxicity in PC12 cells. Brain Res 1996, 723:231–234.

    Article  PubMed  CAS  Google Scholar 

  3. Webster S, Lue LF, Brachova L, et al.: Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer’s disease. Neurobiol Aging 1997, 18:415–421.

    Article  PubMed  CAS  Google Scholar 

  4. McGeer PL, McGeer E, Rogers J, Sibley J: Anti-inflammatory drugs and Alzheimer disease. Lancet 1990, 335:1037.

    Article  PubMed  CAS  Google Scholar 

  5. Breitner JC, Gau BA, Welsh KA, et al.: Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study. Neurology 1994, 44:227–232.

    PubMed  CAS  Google Scholar 

  6. Breitner JC, Welsh KA, Helms MJ, et al.: Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging 1995, 16:523–530.

    Article  PubMed  CAS  Google Scholar 

  7. Stewart WF, Kawas C, Corrada M, Metter EJ: Risk of Alzheimer’s disease and duration of NSAID use. Neurology 1997, 48:626–632.

    PubMed  CAS  Google Scholar 

  8. Veld BA, Ruitenberg A, Hofman A, et al.: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001, 345:1515–1521. This large, longitudinal, epidemiologic study indicates that chronic use of nonsteroidal anti-inflammatory drugs markedly reduces the risk of subsequent Alzheimer’s disease. The study is strengthened by the use of computerized pharmacy records to track drug usage, lessening the issue of recall bias.

    Article  Google Scholar 

  9. Cryer B: Gastrointestinal side effects of nonsteroidal antiinflammatory drugs. Am J Med 1998, 105:20S-30S.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  11. Aisen PS, Marin D, Altstiel L, et al.: A pilot study of prednisone in Alzheimer’s disease. Dementia 1996, 7:201–206.

    PubMed  CAS  Google Scholar 

  12. Fagarasan MO, Sevilla D, Baruch B, et al.: Plasma C3a levels in Alzheimer’s disease. Alzheimer’s Res 1997, 3:137–140.

    CAS  Google Scholar 

  13. Aisen PS, Davis KL, Berg JD, et al.: A randomized controlled trial of prednisone in Alzheimer’s disease. Alzheimer’s Disease Cooperative Study. Neurology 2000, 54:588–593. The first large, randomized, controlled trial of an anti-inflammatory treatment regimen for Alzheimer’s disease. The results were negative.

    PubMed  CAS  Google Scholar 

  14. Aisen PS: Anti-inflammatory therapy for Alzheimer’s disease: implications of the prednisone trial. Acta Neurol Scand 2000, 176(suppl):85–89.

    Article  CAS  Google Scholar 

  15. Hoozemans JJ, Rozemuller AJ, Janssen I, et al.: Cyclooxygenase expression in microglia and neurons in Alzheimer’s disease and control brain. Acta Neuropathol (Berlin) 2001, 101:2–8.

    CAS  Google Scholar 

  16. Iadecola C, Forster C, Nogawa S, Clark HB, Ross ME: Cyclooxygenase-2 immunoreactivity in the human brain following cerebral ischemia. Acta Neuropathol (Berlin) 1999, 98:9–14.

    Article  CAS  Google Scholar 

  17. Tocco G, Freire MJ, Schreiber SS, et al.: Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer’s disease. Exp Neurol 1997, 144:339–349.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Kunz T, Oliw EH: The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci 2001, 13:569–575.

    Article  PubMed  CAS  Google Scholar 

  20. Govoni S, Masoero E, Favalli L, et al.: The Cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat. Neurosci Lett 2001, 303:91–94.

    Article  PubMed  CAS  Google Scholar 

  21. Lim GP, Yang F, Chu T, et al.: Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 2000, 20:5709–5714. This study provides the first evidence that nonsteroidal anti-inflammatory drug treatment can modify the generation of the amyloid peptide in brain.

    PubMed  CAS  Google Scholar 

  22. Lim GP, Yang F, Chu T, et al.: Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging 2001, 22:983–991.

    Article  PubMed  CAS  Google Scholar 

  23. Weggen S, Eriksen JL, Das P, et al.: A subset of NSAIDs lower amyloidogenic AΒ42 independently of cyclooxygenase activity. Nature 2001, 414:212–216. Studies in cell cultures and in transgenic mice indicate that some, but not all, nonsteroidal anti-inflammatory drugs (NSAIDs) influence secretase activity to reduce the generation of toxic amyloid peptides. This finding suggests that the selection of NSAIDs for human testing may be critically important.

    Article  PubMed  CAS  Google Scholar 

  24. Salmeron G, Lipsky PE: Immunosuppressive potential of antimalarials. Am J Med 1983, 75:19–24.

    Article  PubMed  CAS  Google Scholar 

  25. Sperber K, Quraishi H, Kalb TH, itet al.: Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-α) and IL-6 in human monocytes and T cells. 1993, 20:803-808.

  26. DeDuve C, DeBarsy T, Poole B, et al.: Lysosomotropic agents. Biochem Pharmacol 1974, 23:2495–2531.

    Article  CAS  Google Scholar 

  27. Aisen PS, Marin DB, Brickman AM, Santoro J, Fusco M: Pilot tolerability studies of hydroxychloroquine and colchicine in alzheimer disease. Alzheimer Dis Assoc Disord 2001, 15:96–101.

    Article  PubMed  CAS  Google Scholar 

  28. Van Gool WA, Weinstein HC, Scheltens PK, Walstra GJ: Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18-month randomised, doubleblind, placebo-controlled study. Lancet 2001, 358:455–460. Publication of the negative results of the hydroxychloroquine trial, coupled with the similar results with prednisone and celecoxib, has dampened enthusiasm for the anti-inflammatory treatment strategy.

    Article  PubMed  Google Scholar 

  29. Sainati SM, Ingram DM, Talwalker S, Geis GS: Results of a double-blind, randomized, placebo-controlled study of celecoxib in the treatment of progression of Alzheimer’s disease. Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy. Stockholm, Sweden, 2000. This results of this trial of the selective cyclo-oxygenase 2 inhibitor celecoxib were also disappointing.

  30. Steinbach G, Lynch PM, Phillips RK, et al.: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000, 342:1946–1952.

    Article  PubMed  CAS  Google Scholar 

  31. Ho L, Purohit D, Haroutunian V, et al.: Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease. Arch Neurol 2001, 58:487–492.

    Article  PubMed  CAS  Google Scholar 

  32. Landreth GE, Heneka MT: Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheimer’s disease. Neurobiol Aging 2001, 22:937–944.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aisen, P.S. Anti-inflammatory agents in Alzheimer’s disease. Curr Neurol Neurosci Rep 2, 405–409 (2002). https://doi.org/10.1007/s11910-002-0066-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-002-0066-6

Keywords

Navigation