Cyclo-oxygenase-2 inhibitors: rationale and therapeutic potential for Alzheimer's disease

The newly introduced cyclo-oxygenase-2 (COX-2) inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) have been established as effective agents in treating arthritic conditions, while greatly reducing the gastrointestinal adverse effects of traditional NSAIDs. There are expectations that NSAIDs will be useful in the treatment of Alzheimer's disease (AD), and that COX-2 inhibitors might have a role. However, a recently reported clinical trial of a COX-2 inhibitor in AD indicated that it was neither protective nor did it accelerate the decline. The expectations were based on pathological evidence of inflammatory changes associated with AD lesions and epidemiological evidence of a reduced prevalence of AD in populations taking NSAIDs. They were supported by preliminary evidence showing efficacy of NSAIDs in treating patients with AD. These data are based on the use of traditional NSAIDs. Whether COX-2 inhibitors would be similarly effective was uncertain since COX-2 is constitutively expressed in neurons. Animal experiments suggest that COX-2 may be performing adaptive functions associated with normal neurons and protective functions associated with stressed neurons. These results emphasise that the appropriate target for NSAID trials in AD is COX-1, but they also indicate that there would be no contraindication to the use of those traditional NSAIDs which have mixed COX-1/COX-2 inhibiting activity.