Featured Research

from universities, journals, and other organizations

New spin on ibuprofen's actions

Date:
September 26, 2011
Source:
Vanderbilt University Medical Center
Summary:
Ibuprofen, naproxen, and related non-steroidal anti-inflammatory drugs (NSAIDs) -- the subjects of years of study -- still have some secrets to reveal about how they work. Investigators have discovered surprising new insights into the actions of NSAIDs. Their findings raise the possibility of developing a new class of inflammation- and pain-fighting medicines.

Neurons (green) and glial cells from isolated dorsal root ganglia express COX-2 (red) after exposure to an inflammatory stimulus (cell nuclei are blue). Lawrence Marnett and colleagues have demonstrated that certain drugs selectively block COX-2 metabolism of endocannabinoids -- naturally occurring analgesic molecules -- in stimulated dorsal root ganglia.
Credit: Lawrence Marnett and colleagues and Nature Chemical Biology

Ibuprofen, naproxen, and related non-steroidal anti-inflammatory drugs (NSAIDs) -- the subjects of years of study -- still have some secrets to reveal about how they work. Vanderbilt University investigators have discovered surprising new insights into the actions of NSAIDs. Their findings, reported Sept. 25 in Nature Chemical Biology, raise the possibility of developing a new class of inflammation- and pain-fighting medicines.

NSAIDs block the activity of the cyclooxygenase enzymes, COX-1 and COX-2.

"Until about three years ago, we thought we knew everything there was to know about these enzymes and these inhibitors, but we were unaware of some of the details of how they work," said Lawrence Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology and professor of Biochemistry, Chemistry and Pharmacology.

COX-1 and COX-2 oxygenate (add oxygen to) the lipid arachidonic acid to generate biologically active prostaglandins. Marnett and his team discovered about 10 years ago that COX-2 (but not COX-1) also oxygenates endocannabinoids -- naturally occurring analgesic and anti-inflammatory agents that activate cannabinoid receptors (the same receptors that marijuana activates).

The investigators then made a puzzling observation. They found that ibuprofen was a more potent inhibitor of endocannabinoid metabolism compared to arachidonic acid metabolism.

"This was the same drug inhibiting two substrates of the same protein differently," Marnett said. "We didn't understand it."

In the current report, the researchers surveyed a series of different types of NSAIDs for inhibition of COX-2. They included the "mirror-image" versions of ibuprofen, naproxen and flurbiprofen (these drugs come in two different chemical configurations -- a "right hand" (R) version and a "left hand" (S) version -- over-the-counter ibuprofen is a mixture of both forms). It had previously been assumed that only the S-forms of these NSAIDs (S-profens) were able to inhibit COX-2.

Marnett and colleagues found that the R-profens inhibited endocannabinoid, but not arachidonic acid, oxygenation.

The researchers also determined that R-profens selectively block endocannabinoid metabolism in isolated dorsal root ganglia (neurons and glial cells from the spinal column). They found that treatment of these cultures with an inflammatory stimulus increased expression of COX-2 and stimulated release of arachidonic acid and endocannabinoids, which were oxidized by COX-2. The R-profens inhibited metabolism of the endocannabinoids (and increased their concentrations), but not arachidonic acid.

The findings offer a potential explanation for the reported observation that R-flurbiprofen is analgesic in people and that it inhibits neuropathic pain in a mouse model.

"We're proposing that R-flurbiprofen is effective in this neuropathic pain setting because it is preventing the metabolism of endocannabinoids by COX-2; so it's maintaining endocannabinoid tone and that's the basis for the analgesic activity," Marnett said.

"It's exciting because you will only see this effect at sites of inflammation where COX-2 might play a role in depleting endocannabinoids. Selective inhibitors like the R-profens could represent a new way to target analgesia without having the GI, and maybe cardiovascular, side effects of traditional NSAIDs."

Marnett and his team will pursue this idea by studying in vivo models of neuroinflammation to determine if these drugs -- and new compounds they are developing -- work to inhibit endocannabinoid oxidation and maintain endocannabinoid tone.

Kelsey Duggan, Ph.D., Daniel Hermanson, Joel Musee, Ph.D., Jeffery Prusakiewicz, Ph.D., Jami Scheib, Bruce Carter, Ph.D., Surajit Banerjee, Ph.D., and John Oates, M.D., contributed to the studies. The National Institutes of Health (National Institute of General Medical Sciences, National Cancer Institute, and National Institute of Neurological Disorders and Stroke) supported the research.

Marnett is University Professor of Biochemistry and Chemistry, Mary Geddes Stahlman Chair in Cancer Research, and director of the A.B. Hancock Jr. Memorial Laboratory for Cancer Research.


Story Source:

The above story is based on materials provided by Vanderbilt University Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Kelsey C Duggan, Daniel J Hermanson, Joel Musee, Jeffery J Prusakiewicz, Jami L Scheib, Bruce D Carter, Surajit Banerjee, J A Oates, Lawrence J Marnett. (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nature Chemical Biology, 2011; DOI: 10.1038/nchembio.663

Cite This Page:

Vanderbilt University Medical Center. "New spin on ibuprofen's actions." ScienceDaily. ScienceDaily, 26 September 2011. <www.sciencedaily.com/releases/2011/09/110925185443.htm>.
Vanderbilt University Medical Center. (2011, September 26). New spin on ibuprofen's actions. ScienceDaily. Retrieved April 16, 2014 from www.sciencedaily.com/releases/2011/09/110925185443.htm
Vanderbilt University Medical Center. "New spin on ibuprofen's actions." ScienceDaily. www.sciencedaily.com/releases/2011/09/110925185443.htm (accessed April 16, 2014).

Share This



More Health & Medicine News

Wednesday, April 16, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Could Even Casual Marijuana Use Alter Your Brain?

Could Even Casual Marijuana Use Alter Your Brain?

Newsy (Apr. 16, 2014) A new study conducted by researchers at Northwestern and Harvard suggests even casual marijuana use can alter your brain. Video provided by Newsy
Powered by NewsLook.com
Ebola Outbreak Now Linked To 121 Deaths

Ebola Outbreak Now Linked To 121 Deaths

Newsy (Apr. 15, 2014) The ebola virus outbreak in West Africa is now linked to 121 deaths. Health officials fear the virus will continue to spread in urban areas. Video provided by Newsy
Powered by NewsLook.com
Cognitive Function: Is It All Downhill From Age 24?

Cognitive Function: Is It All Downhill From Age 24?

Newsy (Apr. 15, 2014) A new study out of Canada says cognitive motor performance begins deteriorating around age 24. Video provided by Newsy
Powered by NewsLook.com
How Mt. Everest Helped Scientists Research Diabetes

How Mt. Everest Helped Scientists Research Diabetes

Newsy (Apr. 15, 2014) British researchers were able to use Mount Everest's low altitudes to study insulin resistance. They hope to find ways to treat diabetes. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins