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.