Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, are among the most common medications for pain relief, lowering fever and reducing swelling. Most NSAIDs inhibit the cyclooxygenase enzymes COX-1 and COX-2. These enzymes help with the formation of prostaglandins – the ‘pain’ molecules released from damaged tissue. There is increasing evidence that many NSAIDs also have other COX-independent activity, such as limiting the production of proinflammatory cell signaling molecules known as cytokines. Interleukin-1β (IL-1β) is an important cytokine in many inflammatory diseases. IL-1β is activated by the protease caspase-1 enzyme, which in turn is activated as part of a large multi-protein complex known as an inflammasome.
How does this relate to Alzheimer’s treatment?
The best characterized inflammasome is NLRP3 and this inflammasome plays an important role in the brain inflammation of Alzheimer’s patients. Fenamate NSAIDs are a group of approved drugs that have already been shown to inhibit IL-1β secretion, and recent research has shown that this is achieved by inhibition of the NLRP3 inflammasome. Daniels and Rivers-Auty et al. (Nature Communications, 11th August 2016) were able to show that fenamate NSAIDs selectively inhibit the NLRP3 inflammasome in cell culture, while other NSAIDs (e.g. ibuprofen) did not have an effect. In Alzheimer’s disease rat and mouse models, the administration of fenamate NSAIDs completely abated the memory deficits in these animals and removed all Alzheimer’s-related neuroinflammation.
Can fenamate NSAIDs be used to treat Alzheimer’s disease?
This research has shown great promise for the use of fenamate NSAIDs as a way to simultaneously target multiple points in the inflammatory pathway. This means these drugs are likely to be more effective at a lower dose, reducing the risk of adverse side effects. Furthermore, this research has also shown a selective inhibition of the NLRP3 inflammasome, without affecting the functions of other inflammasomes that are essential for a good immune response. So far, researchers have shown the effectiveness of fenamate NSAIDs in treating Alzheimer’s in mouse and rat models, but it has yet to be evaluated in humans. Some fenamate NSAIDs are already routinely used as pain medication, such as mefenamic acid to treat acute pain and menstrual cramps. This study has shown that these commonly prescribed drugs may have added benefits to treat inflammatory diseases, such as Alzheimer’s disease. We eagerly wait for clinical studies to begin!
References:
