Navigation Links
Study puts a new spin on ibuprofen's actions

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.


Contact: Leigh MacMillan
Vanderbilt University Medical Center

Related biology news :

1. University of Arizona to study human-fire-climate interactions
2. Aquarium fishes are more aggressive in reduced environments, a new study finds
3. Harvard School of Public Health awarded $20 million CDC grant to study HIV prevention in Botswana
4. Twin study reveals epigenetic alterations of psychiatric disorders
5. Causes of Gulf War Illness are complex and vary by deployment area -- Baylor University study
6. Study finds bidirectional relationship between schizophrenia and epilepsy
7. CONRAD presents results of pivotal contraceptive study at Reproductive Health 2011
8. Study in underwater laboratory may help manage seaweed-eating fish that protect coral
9. Study finds an increase of children accidentally poisoned with pharmaceuticals
10. UF-led study: Invasive amphibians, reptiles in Florida outnumber world
11. Voting causes stress according to Ben-Gurion University of the Negev study
Post Your Comments:
Related Image:
Study puts a new spin on ibuprofen's actions
(Date:6/23/2017)... and ITHACA, N.Y. , June 23, ... University, a leader in dairy research, today announced a ... to help reduce the chances that the global milk ... of this dairy project, Cornell University has become the ... the Food Supply Chain, a food safety initiative that ...
(Date:5/16/2017)... , May 16, 2017  Veratad Technologies, LLC ... of online age and identity verification solutions, announced today ... Identity Conference 2017, May 15 thru May 17, 2017, ... Building and International Trade Center. Identity ... globe and in today,s quickly evolving digital world, defining ...
(Date:4/24/2017)... -- Janice Kephart , former 9/11 Commission ... LLP (IdSP) , today issues the following statement: ... 6, 2017 Executive Order: Protecting the Nation ... instilled with greater confidence, enabling the reactivation of ... are suspended by until at least July 2017). ...
Breaking Biology News(10 mins):
(Date:10/11/2017)... 2017  VMS BioMarketing, a leading provider of patient support ... Nurse Educator (CNE) network, which will launch this week. The ... health care professionals to enhance the patient care experience by ... other health care professionals to help women who have been ... ...
(Date:10/11/2017)... ... October 11, 2017 , ... Disappearing forests and increased emissions are ... 5.5 million people each year. Especially those living in larger cities are affected by ... in one of the most pollution-affected countries globally - decided to take action. , ...
(Date:10/11/2017)... , ... October 11, 2017 , ... ... (FDA) has granted orphan drug designation to SBT-100, its novel anti-STAT3 (Signal Transducer ... treatment of osteosarcoma. SBT-100 is able to cross the cell membrane and bind ...
(Date:10/10/2017)... , ... October 10, 2017 ... ... cancer-focused pharmaceutical company advancing targeted antibody-drug conjugate (ADC) therapeutics, today confirmed licensing ... HPLN (Hybrid Polymerized Liposomal Nanoparticle), a technology developed in collaboration with Children’s ...
Breaking Biology Technology: