NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ 42 in vivo
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment for a number of neurodegenerative diseases, such as Alzheimer's disease (AD). This idea is supported by epidemiological studies, which show that long -term use of some NSAIDS is associated with reduced incidence of AD. Some NSAIDs have been shown to be γ-secretase modulators; they influence production of the longer more amyloidogenic species of Aβ peptide. To further understand the effects of NSAIDs on Aβ production the authors, in this study, examined the activity of 20 of the most commonly used NSAIDs on Aβ42 levels in cultured H4 human glioma cells and in acute dosing studies in APP transgenic Tg2576 mice. 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.
A phase 2 trial of R-flurbiprofen was undertaken and found that patients with mild AD, but not moderate AD, had a dose-related slower rate of decline than those treated with placebo, and that the drug was well tolerated with few adverse effects. On the basis of these promising results, a large phase 3, randomized, placebo controlled trial of R-flurbiprofen (as known as tarenflurbil) was conducted in patients with mild AD. Disappointing results of the phase 3 trial showed no effect of R-flurbiprofen slowing cognitive decline or loss of activities of daily living in patients with mild AD nor did any secondary outcome measure or post hoc analysis favor the drug.