Anti-inflammatory mechanism leads to development of oral medications for atherosclerosis, IBS

Research led by Charles Nichols, PhD, Associate Professor of Pharmacology at LSU Health Sciences Center New Orleans, describes a powerful new anti-inflammatory mechanism that could lead to the development of new oral medications for atherosclerosis and inflammatory bowel disorders (IBS). The findings are published in PLOS ONE, available online at http://dx.plos.org/10.1371/journal.pone.0075426

One of the master inflammatory molecules in the body is Tumor Necrosis Factor-alpha (TNF-alpha). Infections and certain diseases lead to the production of this molecule, which then stimulates an immune response. Diseases like atherosclerosis, rheumatoid arthritis, and IBS are believed to have inflammation influenced by TNF-alpha as a primary component. Unfortunately, there are no convenient therapeutics to treat inflammation caused by TNF-alpha. Current therapies directed at blocking TNF-alpha inflammation are very expensive antibody treatments that are administered in the clinic.

The research team found that activation of serotonin 5-HT2A receptor proteins potently blocks TNF-alpha induced inflammation. The serotonin 5-HT2A receptor is the main target of classic hallucinogenic drugs like LSD, and the drug the researchers used to activate the receptor protein is itself a member of this class. In the study, the researchers activated serotonin 5-HT2A receptors, and then administered TNF-alpha to mice to produce an inflammatory response. In mice when 5-HT2A receptors were activated before TNF-alpha was administered, there was a near complete blockade of inflammation compared to mice where the 5-HT2A receptors were not activated that had a full inflammatory response. The effects were most powerful in vascular tissues like the aorta, and the intestine. In the intestine, inflammation was blocked with an extremely low dose of the drug - 300 times lower than required for any behavioral effects of the drug.

"Our results potentially represent a breakthrough of a new first in class orally available small molecule-based therapeutic strategy to treat inflammatory diseases involving TNF-alpha," notes Charles Nichols, PhD, Associate Professor of Pharmacology at LSU Health Sciences Center New Orleans. "Although the serotonin 5-HT2A receptor is the primary target for certain drugs, including LSD, to mediate their behavioral effects, the dose of drug necessary for anti-inflammatory effects is orders of magnitude lower than intoxicating doses, and future therapies may target directly the relevant cellular processes activated by the 5-HT2A receptor rather than the receptor itself."

Atherosclerosis, known as hardening of the arteries, is a major cause of coronary heart disease, which is the #1 killer of both men and women in the United States.

According to the National Institute of Diabetes and Digestive and Kidney Diseases, irritable bowel syndrome is estimated to affect 3 to 20 percent of the population, with most studies ranging from 10 to 15 percent. However, less than one-third of people with the condition see a health care provider for diagnosis. IBS affects about twice as many women as men and is most often found in people younger than 45 years. The LSUHSC research team also included Felix Nau, Jr., Bangning Yu, and David A. Martin. The project was supported by a grant ( R21HL095961) from the National Heart, Lung, Blood Institute of the National Institutes of Health.