Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin are widely used to treat pain and inflammation.
But even at similar doses, different NSAIDs can have unexpected and unexplained effects on many diseases, including heart disease and cancer.
Scientists from Yale and elsewhere found a previously unknown process by which some NSAIDs affect the body.
The finding may explain why similar NSAIDs produce a range of clinical outcomes and could inform how the drugs are used in the future.
The research is published in the journal Immunity and was conducted by Anna Eisenstein et al.
Until now, the anti-inflammatory effects of NSAIDs were believed to arise solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs.
In the study, the team uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. And that mechanism may help explain some of these curious effects.
They showed that only some NSAIDs—including indomethacin, which is used to treat arthritis and gout, and ibuprofen—also activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among its many actions, triggers anti-inflammatory processes in the body.
The team is now looking into some of the drugs’ dermatological effects—causing rashes, exacerbating hives, and worsening allergies—and whether they are mediated by NRF2.
This discovery still needs to be confirmed in humans, the researchers note. But if it is, the findings could have an impact on how inflammation is treated and how NSAIDs are used.
For instance, several clinical trials are evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer’s disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs.
Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they’re most likely to treat.
The findings may also point to entirely new applications for NSAIDs.
NRF2 controls a large number of genes involved in a wide range of processes, including metabolism, immune response, and inflammation.
And the protein has been implicated in aging, longevity, and cellular stress reduction.
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