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NEUROPHARMACOLOGY
(1-42) Suppression by Nonsteroidal Anti-Inflammatory Drugs in Young, Plaque-Free Tg2576 Mice and in Guinea Pig Neuronal Cultures
Department of Neurobiology, Pfizer, Inc., Kalamazoo, Michigan
Recent studies indicating that some nonsteroidal anti-inflammatory drugs (NSAIDs) selectively modulate 
-secretase cleavage of amyloid precursor protein (APP) while sparing Notch processing have generated interest in discovery of novel -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 -secretase inhibitors LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(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 A
(1-40) and A(1-42) in the plasma in one of two studies. Flurbiprofen also produced a small reduction in A(1-40) in the cortex at 25 mg/kg/day but did not affect A 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 A(1-42) observed in cell lines overexpressing human mutant APP can be reproduced in a neuronal model of physiological A production and secretion. Flurbiprofen and sulindac nonselectively reduced A(1-40) and A(1-42) at concentrations 
125 µM, although cytotoxicity was noted at 250 µM sulindac. Ibuprofen had no effect at concentrations up to 500 µM. In contrast, DAPT and LY-411575 potently and completely inhibited A(1-40), A(1-42), and A(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 A(1-42) reduction by NSAIDs in neuronal tissue.
Address correspondence to: Dr. Kalpana M. Merchant, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: merchantkm{at}lilly.com
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