New research identifies a previously unknown process that clarifies why similar painkillers such as ibuprofen and aspirin produce a range of clinical outcomes.
Non-steroidal anti-inflammatory drugs (NSAIDs) 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.
Until now, researchers believed the the anti-inflammatory effects of NSAIDs arose solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs.
For example, some NSAIDs prevent heart disease while others cause it; some NSAIDs have been linked to decreased incidence of colorectal cancer; and various NSAIDs can have a wide range of effects on asthma.
Now, using cell cultures and mice, researchers have uncovered a distinct mechanism by which a subset of NSAIDs’ reduce inflammation. And that mechanism may help explain some of these curious effects.
“Because people use NSAIDs so frequently, it’s important we know what they’re doing in the body.”
The research shows 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.
“It’s interesting and exciting that NSAIDs have a different mode of action than what was known previously,” says Anna Eisenstein, an instructor at the Yale University School of Medicine and lead author of the study in the journal Immunity. “And because people use NSAIDs so frequently, it’s important we know what they’re doing in the body.”
The researchers can’t say for sure that NSAIDs unexpected effects are due to NRF2—that will require more research. “But I think these findings are suggestive of that,” Eisenstein says.
Eisenstein 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 affect the treatment of inflammation and NSAID use.
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, Eisenstein says.
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.
“That NRF2 does so much suggests that NSAIDs might have other effects, whether beneficial or adverse, that we haven’t yet looked for,” Eisenstein says.
Source: Mallory Locklear for Yale University
