Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action.
Alzheimer's disease (AD) is characterized by cerebral deposits of beta-amyloid (A beta) peptides and neurofibrillary tangles (NFT) which are surrounded by inflammatory cells. Epidemiological studies have shown that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases (COX) and activation of the peroxisome proliferator-activated receptor gamma. A variety of experimental studies indicate that a subset of NSAIDs such as ibuprofen, flurbiprofen, indomethacin and sulindac also possess A beta-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. While COX inhibition occurs at low concentrations in vitro (nM-low microm range), the A beta-lowering activity is observed at high concentrations (< or = 50 microm). Nonetheless, studies with flurbiprofen or ibuprofen in AD transgenic mice show that the effects on A beta levels or deposition are attained at plasma levels similar to those achieved in humans at therapeutic dosage. Still, it remains to be assessed whether adequate concentrations are reached in the brain. This is a crucial aspect that will allow defining the dose-window and the length of treatment in future clinical trials. Here, we will discuss how the combination of anti-amyloidogenic and anti-inflammatory activities of certain NSAIDs may produce a profile potentially relevant to their clinical use as disease-modifying agents for the treatment of AD.
Gasparini
Laura
L
Nicox Research Institute, 20091 Bresso, Milan, Italy.
Ongini
Ennio
E
Wenk
Gary
G
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000682:Amyloid / Q000096:biosynthesis / Q000187:drug effects; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047495:PPAR gamma / Q000378:metabolism
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D047495:PPAR gamma