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Citations to this article

NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Jason L. Eriksen, … , Edward H. Koo, Todd E. Golde
Jason L. Eriksen, … , Edward H. Koo, Todd E. Golde
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):440-449. https://doi.org/10.1172/JCI18162.
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Article Neuroscience Article has an altmetric score of 15

NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo

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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 β protein (Aβ42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid β protein precursor (APP) transgenic mice, and plasma and brain levels of Aβ and the drug were evaluated. These studies show that (a) eight FDA-approved NSAIDs lower Aβ42 in vivo, (b) the ability of an NSAID to lower Aβ42 levels in cell culture is highly predicative of its in vivo activity, (c) in vivo Aβ42 lowering in mice occurs at drug levels achievable in humans, and (d) there is a significant correlation between Aβ42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Aβ42 levels in broken cell γ-secretase assays, indicating that these compounds directly target the γ-secretase complex that generates Aβ from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Aβ42 levels to the greatest extent. Because R-flurbiprofen reduces Aβ42 levels by targeting γ-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Aβ42 lowering agent.

Authors

Jason L. Eriksen, Sarah A. Sagi, Tawnya E. Smith, Sascha Weggen, Pritam Das, D.C. McLendon, Victor V. Ozols, Kevin W. Jessing, Kenton H. Zavitz, Edward H. Koo, Todd E. Golde

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 Total
Citations: 3 6 6 6 11 11 7 6 8 6 9 12 16 18 18 22 18 18 11 9 8 2 1 232
Citation information
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Citations to this article in year 2010 (22)

Title and authors Publication Year
A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons
J Dill, AR Patel, XL Yang, R Bachoo, CM Powell, S Li
The Journal of neuroscience : the official journal of the Society for Neuroscience 2010
R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids
P Bishay, H Schmidt, C Marian, A Häussler, N Wijnvoord, S Ziebell, J Metzner, M Koch, T Myrczek, I Bechmann, R Kuner, M Costigan, F Dehghani, G Geisslinger, I Tegeder
PloS one 2010
Molecular Mechanism for Various Pharmacological Activities of NSAIDS
T Mizushima
Pharmaceuticals (Basel, Switzerland) 2010
Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease
GS Basi, S Hemphill, EF Brigham, A Liao, DL Aubele, J Baker, R Barbour, M Bova, XH Chen, MS Dappen, T Eichenbaum, E Goldbach, J Hawkinson, R Lawler-Herbold, K Hu, T Hui, JJ Jagodzinski, PS Keim, D Kholodenko, LH Latimer, M Lee, J Marugg, MN Mattson, S McCauley, JL Miller, R Motter, L Mutter, ML Neitzel, H Ni, L Nguyen, K Quinn, L Ruslim, CM Semko, P Shapiro, J Smith, F Soriano, B Szoke, K Tanaka, P Tang, JA Tucker, XM Ye, M Yu, J Wu, YZ Xu, AW Garofalo, JM Sauer, AW Konradi, D Ness, G Shopp, MA Pleiss, SB Freedman, D Schenk
Alzheimer's research & therapy 2010
A potential nitrergic mechanism of action for indomethacin, but not of other COX inhibitors: relevance to indomethacin-sensitive headaches
O Summ, AP Andreou, S Akerman, PJ Goadsby
The Journal of Headache and Pain 2010
Brain amyloid β protein and memory disruption in Alzheimer's disease
W Xia
Neuropsychiatric Disease and Treatment 2010
The Nuclear Receptor PPARgamma as a Therapeutic Target for Cerebrovascular and Brain Dysfunction in Alzheimer's Disease
N Nicolakakis, E Hamel
Frontiers in aging neuroscience 2010
NSAIDs: How they Work and their Prospects as Therapeutics in Alzheimer's Disease
M Sastre, SM Gentleman
Frontiers in aging neuroscience 2010
Presenilin/gamma-Secretase and Inflammation
CA Saura
Frontiers in aging neuroscience 2010
Targeting Abeta and tau in Alzheimer's disease, an early interim report
TE Golde, L Petrucelli, J Lewis
Experimental Neurology 2010
Amyloid-modifying therapies for Alzheimer’s disease: therapeutic progress and its implications
MC Creed, NW Milgram
AGE 2010
Lost in Translation: Neuropsychiatric Drug Development
RE Becker, NH Greig
Science Translational Medicine 2010
Drug Development for Alzheimer's Disease: Recent Progress
W Ji, I Ha
Experimental Neurobiology 2010
Tarenflurbil: mechanisms and myths
M Sano
Archives of neurology 2010
Diclofenac-induced stimulation of SMCT1 (SLC5A8) in a heterologous expression system: A RPE specific phenomenon
S Ananth, L Zhuang, E Gopal, S Itagaki, B Ellappan, SB Smith, V Ganapathy, P Martin
Biochemical and Biophysical Research Communications 2010
Effects of nonsteroidal anti-inflammatory drugs on amyloid-β pathology in mouse skeletal muscle
TL Beckett, DM Niedowicz, CM Studzinski, AM Weidner, RL Webb, CJ Holler, RR Ahmed, H LeVine, MP Murphy
Neurobiology of Disease 2010
R-flurbiprofen improves axonal transport in the Tg2576 mouse model of Alzheimer's Disease as determined by MEMRI
KD Smith, R Paylor, RG Pautler
Magnetic Resonance in Medicine 2010
Biomarkers in Alzheimer's disease drug development
K Blennow
Nature Medicine 2010
Bepridil and Amiodarone Simultaneously Target the Alzheimer's Disease - and -Secretase via Distinct Mechanisms
S Mitterreiter, RM Page, F Kamp, J Hopson, E Winkler, HR Ha, R Hamid, J Herms, TU Mayer, DJ Nelson, H Steiner, T Stahl, U Zeitschel, S Rossner, C Haass, SF Lichtenthaler
The Journal of neuroscience : the official journal of the Society for Neuroscience 2010
β-Amyloid Precursor Protein Mutants Respond to γ-Secretase Modulators
RM Page, A Gutsmiedl, A Fukumori, E Winkler, C Haass, H Steiner
The Journal of biological chemistry 2010
Neuroinflammatory processes in Alzheimer’s disease
MT Heneka, MK OBanion, D Terwel, MP Kummer
Journal of Neural Transmission 2010
Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease.
Cole GM, Frautschy SA
CNS & neurological disorders drug targets 2010

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