Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyloid beta-Peptides / analysis
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Amyloid beta-Peptides / antagonists & inhibitors*
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Blotting, Western
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Cell Line
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Culture Media, Conditioned / chemistry
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Culture Media, Conditioned / metabolism
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Dose-Response Relationship, Drug
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Flurbiprofen / pharmacology
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Humans
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Ibuprofen / pharmacology
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Kidney / cytology
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Kidney / drug effects
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Kidney / metabolism
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Mutation
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Peptide Fragments / analysis
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Peptide Fragments / antagonists & inhibitors*
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Peptide Fragments / metabolism*
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Peptides / pharmacology
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Stereoisomerism
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Transfection
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Anti-Inflammatory Agents, Non-Steroidal
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Culture Media, Conditioned
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NF-kappa B
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Peptide Fragments
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Peptides
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SN50 peptide
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Flurbiprofen
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Ibuprofen