Selective inhibition of Abeta42 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 (Abeta) accumulation in vivo and Abeta42 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 Abeta42 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 Abeta42 production by human cells. Although these R-enantiomers inhibit nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB can selectively regulate Abeta42, Abeta42 reduction is not mediated by inhibition of NF-kappaB activation. Because of its efficacy at lowering Abeta42 production and low toxicity profile, R-flurbiprofen is a strong candidate for clinical development.
Morihara
T
T
Department of Medicine, University of California, Los Angeles, California, USA.
Chu
T
T
Ubeda
O
O
Beech
W
W
Cole
G M
GM
D016229:Amyloid beta-Peptides / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005480:Flurbiprofen / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D013237:Stereoisomerism; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D010446:Peptide Fragments; D010455:Peptides; C118258:SN50 peptide; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen; D007052:Ibuprofen