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Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice


Year of Publication:
Contact PI Name:
Michelle M. Nicolle
Contact PI Affiliation:
Departments Internal Medicine/Gerontology and the Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
Thomas Kukar, Sonya Prescot, Jason L. Eriksen, Vallie Holloway, M. Paul Murphy, Edward H. Koo, Todd E. Golde
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
Mayo Foundation
John Douglas French Foundation
Smith Fellowship in Neurological Disease Research
Study Goal and Principal Findings:

 Extensive screening of NSAIDs, NSAID-derivatives and related compounds led to the identification of R-flurbiprofen as a promising selective Aβ42-lowering agent. R-Flurbiprofen is a purified enantiomer of the classical racemic NSAID flurbiprofen, which displays minimal COX activity and does not undergo stereoinversion in humans. R-flurbiprofen was observed to lower Aβ42 in cell culture and in the brain of young non-depositing Tg2576 APP mice following 3-days of oral dosing Based on R-flurbiprofen's selective lowering of Aβ42, reduced COX activity and safety profile in humans the authors suggested that this drug was a good candidate for clinical testing in AD.

In this study the authors report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in a transgenic model of AD- Tg2576 APP mice. In two separate behavioral trials, long-term treatment initiated in young Tg2576 mice with 10 mg/kg/day R-flurbiprofen improved spatial learning as assessed by the Morris water maze (WM). A modest reduction in biochemical Aβ loads was also observed, though this did not reach statistical significance in either study. A 2-week treatment of older Tg2576 with the same dose of R-flurbiprofen decreased Aβ plaque levels (p < 0.0001) but did not result in any significant alteration in spatial learning.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
gamma Secretase
Therapeutic Notes:
R-Flurbiprofen is the R-enantiomer of the NSAID Flurbiprofen. It is not a cyclooxygenase (COX 1/COX 2) inhibitor. R-Flurbiprofen has recently been shown to modulate gamma secretase and selectively lower levels of Aβ42 and amyloid pathology in vivo. R-Flurbiprofen also modulates NFκB signaling pathways.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
beta Amyloid Load
Brain-Detergent Soluble beta Amyloid Peptide 40
Brain-Detergent Soluble beta Amyloid Peptide 42
Brain-Formic Acid Soluble beta Amyloid Peptide 40
Brain-Formic Acid Soluble beta Amyloid Peptide 42
Drug Concentration-Brain
Body Weight
General Health