Serotonin 5-HT2A Receptor Activation Blocks TNF-α Mediated Inflammation In Vivo
Summary & key facts
Researchers gave an experimental drug called (R)-DOI, which turns on a specific serotonin receptor known as 5-HT2A, to animals and then triggered inflammation with a molecule called tumor necrosis factor alpha or TNF-alpha. The drug strongly reduced signs of inflammation in the aorta and small intestine, and it stopped the usual rise in a blood inflammatory signal called IL-6. The work was done in animals and lab tests, so it suggests a new way that drugs acting on the 5-HT2A serotonin receptor might one day help treat inflammatory diseases, but it is early and not tested in people.
- TNF-alpha is a chemical in the body that helps drive inflammation and is linked to many inflammatory diseases.
- The researchers used (R)-DOI, a drug that activates the serotonin 5-HT2A receptor, and gave it to whole animals before or during TNF-alpha exposure.
- (R)-DOI strongly reduced inflammation-related gene activity in the aortic arch and the small intestine of the treated animals.
- The drug blocked increases in several inflammation markers, including cell adhesion genes Icam-1 and Vcam-1, cytokine genes Il-6 and Il-1b, and chemokine genes Mcp-1 and Cx3cl1.
- (R)-DOI also prevented the rise of IL-6 levels in the blood and reduced the intestinal protein VCAM-1 that is linked to inflammation.
- The anti-inflammatory effect depended on activating the 5-HT2A serotonin receptor, because drugs that block that receptor stopped the effect.
- These results come from animal experiments and lab measurements. They do not show that the same effect will happen in humans yet.
- The authors suggest this receptor could be a target for new small-molecule drugs to treat inflammatory conditions such as atherosclerosis and inflammatory bowel disease, but more research is needed.
Abstract
Tumor necrosis factor alpha (TNF-α) plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective activation of serotonin 5-HT2A receptors with the agonist (R)-DOI produces a super-potent blockade of proinflammatory markers in primary rat aortic smooth muscle cells. Here, we demonstrate that systemic administration of (R)-DOI can block the systemic effects of TNF-α in whole animal, with potent anti-inflammatory effects in the aortic arch and small intestine. This includes blockade of TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1), cytokine (Il-6, IL-1b), and chemokine (Mcp-1, Cx3cl1) genes, and expression of VCAM-1 protein in the intestine. Further, systemic (R)-DOI also prevents the TNF-α-induced increase of circulating IL-6. Importantly, utilizing receptor selective antagonists, we have demonstrated that the mechanism underlying the systemic anti-inflammatory effects of (R)-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases and conditions such as atherosclerosis and inflammatory bowel disease.
