Selective inhibition of A beta 42 production by NSAID R-enantiomers

Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced risk for Alzheimer's disease (AD) and selected NSAIDs racemates suppress beta -amyloid (A beta ) accumulation in vivo and A beta 42 production in vitro. Clinical use of NSAIDs for preventing or treating AD has been hampered by dose-limiting toxicity believed to be due to cyclooxygenase (COX)-inhibition that is reportedly not essential for selective A beta 42 reduction. Profens have racemates and R-enantiomers were supposed to be inactive forms. Here we demonstrate that R-ibuprofen and R-flurbiprofen, with poor COX-inhibiting activity, reduce A beta 42 production by human cells. Although these R-enantiomers inhibit nuclear factor- mu B (NF- mu B) activation and NF- mu B can selectively regulate A beta 42, A beta 42 reduction is not mediated by inhibition of NF- mu B activation. Because of its efficacy at lowering A beta 42 production and low toxicity profile, R-flurbiprofen is a strong candidate for clinical development.