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.