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. 2010 May 18:2:20.
doi: 10.3389/fnagi.2010.00020. eCollection 2010.

NSAIDs: How they Work and their Prospects as Therapeutics in Alzheimer's Disease

Magdalena Sastre  1 , Steve M Gentleman
Affiliations

NSAIDs: How they Work and their Prospects as Therapeutics in Alzheimer's Disease

Magdalena Sastre et al. Front Aging Neurosci. .

Abstract

There is significant epidemiological evidence to suggest that there are beneficial effects of treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease, although these effects have not been reproduced in clinical trials. The failure of the clinical trials may be attributed to several possible facts: (1) NSAIDS may have been delivered too late to patients, as they may only be effective in early stages of the disease and possibly counterproductive in the late stages; (2) the beneficial effect may depend on the drug, because different NSAIDs may have different molecular targets; (3) the NSAID concentration reaching the brain and the duration of the treatment could also be critical, so increasing drug penetration is important in order to improve the efficacy and avoid secondary gastro-intestinal effects of the NSAIDs. In this report we analyze these different factors, with special emphasis on the role of NSAIDs in microglia activation over time.

Keywords: Alzheimer's disease; NSAIDs; PPARγ; amyloid; microglia.

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Figures

Figure 1
Figure 1
Different targets for NSAIDs. The response to NSAIDs may differ depending on whether they are used in early stages of disease, in which microglia present an alternatively activated phenotype compared with late stages which is associated with a classical microglia phenotype. On the other hand, different subsets of NSAIDs have different affinity for targets such as COX1, COX2, NFκB, PPARγ or γ-secretase, resulting in a range of effects including reductions in inflammatory mediators, such as cytokines and alterations in Aβ generation.
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