Activity of flurbiprofen and chemically related anti-inflammatory drugs in models of Alzheimer's disease.
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 beta-amyloid (Abeta) deposition and metabolism. Among the Abeta-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.
Gasparini
Laura
L
Nicox Research Institute, Bresso, Milan, Italy.
Ongini
Ennio
E
Wilcock
Donna
D
Morgan
David
D
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D017628:Microglia / Q000187:drug effects; D013329:Structure-Activity Relationship
C450321:(3-4-(2-fluoromethyl-(1,1'-biphenyl)-4-acetyloxy)-3-methoxyphenyl)-2-propenoic acid 4-nitrooxy butyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; C095631:nitroflurbiprofen; D005480:Flurbiprofen