Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs.
Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia in the elderly. The AD brain pathology is characterized by deposits of amyloid-beta (Abeta) peptides and neurofibrillary tangles but also (among other aspects) by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. Classical targets of NSAIDs include cycloxygenase, nuclear factor kappaB, and peroxisome proliferator-activated receptors. Modulation of these pathways, all of which have been implicated in AD pathogenesis, could explain the NSAID effect on AD progression. However, recent studies indicate that a subset of NSAIDs such as ibuprofen, indomethacin, and flurbiprofen may have direct Abeta-lowering properties in cell cultures as well as transgenic models of AD-like amyloidosis. A renewed interest in the old and a discovery of new pharmacological properties of these drugs are providing vital insight for future clinical trials. In this review we will summarize how the combination of traditional (anti-inflammatory) and new (anti-amyloidogenic) properties of some NSAIDs is providing unprecedented opportunities for drug discovery and could potentially result in novel therapeutic approaches for the treatment of AD.
Townsend
Kirk P
KP
Center for Experimental Therapeutics and Department of Pharmacology; University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA.
Praticò
Domenico
D
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D018929:Cell Culture Techniques; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005480:Flurbiprofen / Q000627:therapeutic use; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D007213:Indomethacin / Q000627:therapeutic use; D007249:Inflammation; D008954:Models, Biological; D008956:Models, Chemical; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D047495:PPAR gamma; D010455:Peptides; D047492:Peroxisome Proliferator-Activated Receptors; D005480:Flurbiprofen; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen; D007213:Indomethacin