RESUMO
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.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/análise , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Western Blotting , Linhagem Celular , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/metabolismo , Relação Dose-Resposta a Droga , Flurbiprofeno/farmacologia , Humanos , Ibuprofeno/farmacologia , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Mutação , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Fragmentos de Peptídeos/análise , Peptídeos/farmacologia , Estereoisomerismo , TransfecçãoRESUMO
We previously showed the non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppresses inflammation and amyloid in the APPsw (Tg2576) Tg2576 transgenic mouse. The mechanism for these effects and the impact on behavior are unknown. We now show ibuprofen's effects were not mediated by alterations in amyloid precursor protein (APP) expression or oxidative damage (carbonyls). Six months ibuprofen treatment in Tg+ females caused a decrease in open field behavior (p < 0.05), restoring values similar to Tg- mice. Reduced caspase activation per plaque provided further evidence for a neuroprotective action of ibuprofen. The impact of a shorter 3 month duration ibuprofen trial, beginning at a later age (from 14 to 17 months), was also investigated. Repeated measures ANOVA of Abeta levels (soluble and insoluble) demonstrated a significant ibuprofen treatment effect (p < 0.05). Post-hoc analysis showed that ibuprofen-dependent reductions of both soluble Abeta and Abeta42 were most marked in entorhinal cortex (p < 0.05). Although interleukin-1beta and insoluble Abeta were more effectively reduced with longer treatment, the magnitude of the effect on soluble Abeta was not dependent on treatment duration.
Assuntos
Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Ibuprofeno/farmacologia , Envelhecimento/patologia , Envelhecimento/psicologia , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Interleucina-1/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Oxirredução , Caracteres SexuaisRESUMO
The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene-positive (Tg+) and negative (Tg-) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1beta and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of beta-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble Abeta. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of anti-phosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.
