Review Activity of flurbiprofen and chemically related anti-inflammatory drugs in models of Alzheimer’s disease Laura Gasparini a,b , Ennio Ongini a, * , Donna Wilcock c , David Morgan c a Nicox Research Institute, Via Ariosto 21, 20091 Bresso, Milan, Italy b Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK c Alzheimer’s Research Laboratory, Department of Pharmacology, University of South Florida, Tampa, FL 33612, USA Accepted 9 December 2004 Available online 28 January 2005 Abstract Currently, there is an intense debate on the potential use of nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease (AD). NSAIDs are among the most widely prescribed drugs for the treatment of pain, fever, and inflammation. Their effects are largely attributed to the inhibition of the enzymatic activity of cyclooxygenase (COX)-1 and -2. The apparent activity of this class of drugs stems from one critical pathological process underlying AD and other neurodegenerative disorders, i.e., the presence of chronic neuroinflammation. In fact, prolonged use of NSAIDs is associated with reduced risk of AD. Besides COX inhibition, additional mechanisms could contribute to the potential activity of NSAIDs in AD. For example, several studies show that only a few selected NSAIDs also affect h-amyloid (Ah) deposition and metabolism. Among the Ah-effective NSAIDs, flurbiprofen raised particular interest because of its multiple actions on key AD hallmarks. Studies in cell lines and animal models have shown that flurbiprofen racemate, its R-enantiomer and its nitric oxide (NO)- releasing derivatives, HCT 1026 and NCX 2216, are effective on AD amyloid pathology. Moreover, HCT 1026 and NCX 2216 differentially influence the cellular component of neuroinflammation (i.e., microglia activation) in some experimental settings, i.e., HCT 1026 inhibits the activation of microglia, while NCX 2216 can either enhance or inhibit microglial activation, depending upon the experimental conditions. It is still unclear which effects on microglia will prove most beneficial. Ultimately, clinical studies in AD patients will provide the best information as to whether selected NSAIDs will improve this devastating disease. D 2004 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Degenerative disease: Alzheimer’s-h-amyloid Keywords: NSAIDs; Flurbiprofen; HCT 1026; NCX 2216; Microglia; Alzheimer’s disease Contents 1. Clinical evidence supporting NSAIDs in AD .......................................... 401 2. Only certain NSAIDs show activity against h-amyloid ..................................... 401 3. Effects of flurbiprofen and its derivatives on the cellular components of inflammation ..................... 402 4. Differential effects of HCT 1026 and NCX 2216 on microglia ................................. 404 5. Enhancement or inhibition of microglia activation? ....................................... 405 6. Concluding remarks ....................................................... 406 Acknowledgments ........................................................... 406 References ............................................................... 406 0165-0173/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2004.12.029 * Corresponding author. Fax: +39 02 61036430. E-mail address: ongini@nicox.it (E. Ongini). Brain Research Reviews 48 (2005) 400 – 408 www.elsevier.com/locate/brainresrev