Lack of specific amyloid-beta(1-42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures.
Recent studies indicating that some nonsteroidal anti-inflammatory drugs (NSAIDs) selectively modulate gamma-secretase cleavage of amyloid precursor protein (APP) while sparing Notch processing have generated interest in discovery of novel gamma-secretase modulators with the "NSAID-like" efficacy profile. The objective of the present studies was to compare the efficacy of a subset of NSAIDs with previously reported classical gamma-secretase inhibitors LY-411575 [N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]and DAPT [N-[N- (3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester] in Tg2576 mice. Flurbiprofen (10 and 25 mg/kg/day) was overtly toxic and elicited significant (but nonselective) reductions in both Abeta(1-40) and Abeta(1-42) in the plasma in one of two studies. Flurbiprofen also produced a small reduction in Abeta(1-40) in the cortex at 25 mg/kg/day but did not affect Abeta levels in hippocampus or cerebrospinal fluid. Ibuprofen and sulindac sulfide were neither overtly toxic nor efficacious at doses up to 50 mg/kg/day. The effects of NSAIDs LY-411575 and DAPT were tested in guinea pig embryonic neuronal cultures to determine whether the selective reductions in Abeta(1-42) observed in cell lines overexpressing human mutant APP can be reproduced in a neuronal model of physiological Abeta production and secretion. Flurbiprofen and sulindac nonselectively reduced Abeta(1-40) and Abeta(1-42) at concentrations > or =125 microM, although cytotoxicity was noted at > or =250 microM sulindac. Ibuprofen had no effect at concentrations up to 500 microM. In contrast, DAPT and LY-411575 potently and completely inhibited Abeta(1-40), Abeta(1-42), and Abeta(1-38) in the absence of cytotoxicity. The divergence of the present data from published reports raises the need to examine the conditions necessary to perceive selective Abeta(1-42) reduction by NSAIDs in neuronal tissue.
Lanz
Thomas A
TA
Department of Neurobiology, Pfizer, Inc., Kalamazoo, Michigan, USA.
Fici
Gregory J
GJ
Merchant
Kalpana M
KM
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D058225:Plaque, Amyloid
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)