The goal of this study was to test the working hypothesis that the benefit of NSAID use in diminishing the risk of AD is attributable to suppression of the microglial response. To this end the authors compared the effects of ibuprofen, a prototypical and nonselective NSAID with celecoxib, a COX2-selective inhibiting NSAID, and the NO-releasing derivative of the COX1 NSAID flurbiprofen - NCX-2216, on beta amyloid deposition and microglial activation in the APP/PS1 mouse model of beta amyloid deposition. Results found that NCX-2216 dramatically reduced both beta-amyloid load and Congo red staining in APP/PS1 mice when administered at 375 ppm in diet between 7 and 12 months of age. This reduction was associated with a dramatic increase in the number of microglia expressing major histocompatibility complex-II antigen(MHC-II), a marker for microglial activation. In contrast, treatment with ibuprofen, administered at 375 ppm in diet,between 7-12 months of age, caused modest reductions in Abeta load but not Congo red staining, suggesting that the effects of this nonselective NSAID were restricted primarily to nonfibrillar deposits. Ibuprofen treatment was not associated with increase in the number microglia expressing the MHC-II marker of microglial activation. Celecoxib administered at 175ppm in diet at 7-12 months of age had no effect on either beta amyloid load, Congo red straining or, the number of activated microglia. In short-term studies of 12-month-old Tg mice, data showed that the microglia-activating properties of NCX-2216 were present after 2 weeks of treatment. Microglia were not activated by NCX-2216 in non-Tg mice lacking Abeta deposits, nor were microglia activated in Tg animals by flurbiprofen. In conclusion, these data identify an unexpected activation of microglia by a nitro-NSAID in a mouse model of amyloid deposition and imply that the NO-generating component of NCX-2216 confers biological activities that go beyond those of typical NSAIDs. These results may impact the design of human trials to evaluate these drugs as therapeutics in AD patients.
In the long-term administration study, we selected the dosage of ibuprofen (375 ppm in diet or ~62.5 mg / kg 1 / d 1 per animal; n = 7 transgenic and 8 nontransgenic mice) that Lim et al. (J Neurosci 20:5709–5714,2000) found to be effective at reducing A. We estimated an equivalent dosage of celecoxib (175 ppm or ~30 mg/ kg 1 / d 1 per animal; n = 7 transgenic and 7 nontransgenic mice) based on the relative human daily dosages of celecoxib and ibuprofen. We similarly estimated an equivalent dosage of NCX-2216 (375 ppm in diet or ~62.5 mg / kg 1 / d 1 per animal; n =7 transgenic mice) so that the ratio of the mass of flurbiprofen consumed relative to ibuprofen in the first diet would approximate the relative human dosages of these drugs.