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NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.
J Clin Invest. 2003 Aug; 112(3):440-9.JCI

Abstract

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.

Authors+Show Affiliations

Department of Neuroscience, Mayo Graduate School, Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12897211

Citation

Eriksen, Jason L., et al. "NSAIDs and Enantiomers of Flurbiprofen Target Gamma-secretase and Lower Abeta 42 in Vivo." The Journal of Clinical Investigation, vol. 112, no. 3, 2003, pp. 440-9.
Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest. 2003;112(3):440-9.
Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., & Golde, T. E. (2003). NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. The Journal of Clinical Investigation, 112(3), 440-9.
Eriksen JL, et al. NSAIDs and Enantiomers of Flurbiprofen Target Gamma-secretase and Lower Abeta 42 in Vivo. J Clin Invest. 2003;112(3):440-9. PubMed PMID: 12897211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. AU - Eriksen,Jason L, AU - Sagi,Sarah A, AU - Smith,Tawnya E, AU - Weggen,Sascha, AU - Das,Pritam, AU - McLendon,D C, AU - Ozols,Victor V, AU - Jessing,Kevin W, AU - Zavitz,Kenton H, AU - Koo,Edward H, AU - Golde,Todd E, PY - 2003/8/5/pubmed PY - 2003/9/13/medline PY - 2003/8/5/entrez SP - 440 EP - 9 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 112 IS - 3 N2 - Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/12897211/NSAIDs_and_enantiomers_of_flurbiprofen_target_gamma_secretase_and_lower_Abeta_42_in_vivo_ L2 - https://doi.org/10.1172/JCI18162 DB - PRIME DP - Unbound Medicine ER -