Therapeutics

Ibuprofen

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Overview

Name: Ibuprofen
Synonyms: Advil™, Nuprin™ , Motrin™
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Approved for: Pain and Fever

Background

Ibuprofen is an over-the-counter non-steroidal anti-inflammatory drug (NSAID). It inhibits cyclooxygenase activity and reduces inflammation through reduced prostaglandin synthesis. 

In the Alzheimer's field, interest in NSAIDs such as ibuprofen arose when epidemiological studies started reporting lower rates of Alzheimer's among people who had been taking these drugs for chronic treatment of inflammatory conditions (e.g., Mar 1997 news story; in't Veld et al., 1998; Nov 2001 news story; Vlad et al., 2008). Interest grew when ibuprofen was shown to be part of a subset of NSAIDs that reduce Aβ42 levels by modulating the activity of the γ-secretase enzyme complex. The protective epidemiological effect of these NSAIDs was then attributed to this γ-secretase modulating activity, not their cyclooxygenase inhibition (Nov 2001 news story).

In subsequent years, a host of experimental studies reported Aβ-lowering effects of NSAIDS including ibuprofen, in cell-based and animal models of Alzheimer's disease (e.g., Aug 2000 news story; Sep 2004 news story)

Findings

Because of its known gastrointestinal toxicity and low exposure in the brain, few clinicial trials have evaluated ibuprofen for the treatment of Alzheimer's disease. In 2003 and 2004, a one-year, multicenter trial compared 400 mg of ibuprofen twice daily to placebo in 132 people with mild to moderate AD. Outcomes included the ADAS-cog, MMSE, CDR, and other standard measures. There was no difference between the ibuprofen and placebo groups on any outcome (Pasqualetti et al., 2009).

A subsequent meta-analysis of clinical trials of NSAIDs including ibuprofen confirmed that the NSAID groups had no significant cognitive benefit, but more nausea and vomiting, and that ibuprofen cannot be recommended for the treatment of Alzheimer's disease (Jaturapatporn et al., 2012). More broadly, randomized clinical trials of NSAIDs as therapeutic approaches to Alzheimer's disese have been negative and remain at odds with the epidemiological observations (May 2008 news story).

Early research on ibuprofen shifted attention to a structurally related compound, R-flurbiprofen. This drug was clinically evaluated through Phase 3, where it failed.

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References

News Citations

  1. NSAIDs in AD: Epi and Trial Data at Odds—Again
  2. Ibuprofen Linked to Reduced Alzheimer's Risk
  3. Large Prospective Study Finds NSAIDs Reduce Risk of Developing AD
  4. Anti-inflammatory Drugs Side-Step COX Cascade to Target Aβ
  5. Ibuprofen Reduces Plaques and Inflammation in "Hsiao" Mice
  6. FRETting Pays off—NSAIDs Target Presenilins, Reduce Aβ42

Therapeutics Citations

  1. Flurizan™

Paper Citations

  1. . A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease. Aging Clin Exp Res. 2009 Apr;21(2):102-10. PubMed.
  2. . Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst Rev. 2012;2:CD006378. PubMed.
  3. . NSAIDs and incident Alzheimer's disease. The Rotterdam Study. Neurobiol Aging. 1998 Nov-Dec;19(6):607-11. PubMed.
  4. . Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008 May 6;70(19):1672-7. PubMed.

Further Reading

Papers

  1. . Nonsteroidal anti-inflammatory drugs exposure and the central nervous system. Handb Clin Neurol. 2014;119:577-84. PubMed.
  2. . γ-secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes. Curr Top Med Chem. 2011;11(12):1555-70. PubMed.
  3. . Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain. J Biol Chem. 2003 Aug 15;278(33):30748-54. PubMed.
  4. . Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science. 2003 Nov 14;302(5648):1215-7. PubMed.