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Antidepressants Could Stop Deadly Sepsis

Summary: A new study reports fluvoxamine, an antidepressant used to treat OCD appears to be effective in stopping sepsis.

Source: University of Virginia Health System.

An antidepressant drug used to treat obsessive-compulsive disorder could save people from deadly sepsis, new research from the University of Virginia School of Medicine suggests.

Sepsis is a significant cause of death around the world. The federal Centers for Disease Control and Infection calls it “the body’s extreme response to an infection.” Essentially, the body’s immune response spirals out of control, and the normally beneficial inflammation becomes harmful. The result can be tissue damage, organ failure or even death.

“Sepsis is very dangerous. In the U.S., 1.7 million get it every year, and 270,000 people die,” said researcher Alban Gaultier, PhD, of UVA’s Department of Neuroscience and its Center for Brain Immunology and Glia (BIG). “Once you get diagnosed, you have a high chance of mortality. And there is no good treatment. Basically, we will try to keep you alive and monitor you as much as we can. So clearly there is a critical need for treatment.”

Gaultier and his team have identified a drug that could offer that treatment – and previous safety testing of the drug could fast-track it into use in hospitals around the country.

A Simple Solution for Sepsis?

The UVA researchers were looking at a little-studied biological process inside our cells when they determined it has an important role in regulating inflammation. They began studying it partly because there are already drugs that can affect players in the process.

“Inflammation, most of the time, is good. It’s when it gets out of control that we need to modulate it,” Gaultier said. “Inflammation is a very precisely controlled reaction. When we need it and have too much, it’s a problem, but when we don’t have enough, it’s also a problem.”

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Gaultier and his team have identified a drug that could offer that treatment – and previous safety testing of the drug could fast-track it into use in hospitals around the country. NeuroscienceNews.com image is in the public domain.

To evaluate the potential of one drug, the antidepressant fluvoxamine, to stop sepsis, Gaultier’s team tested it in a mouse model of the disease. The drug worked very effectively, they found.

While the drug will need to be tested in people to determine its effectiveness at battling human sepsis, previous testing to determine its safety should accelerate that process.

Gaultier hypothesizes that the same biological process could be targeted to generate beneficial inflammation when needed, such as in immunocompromised people. “By inhibiting the receptor, we could activate inflammation in conditions where patient don’t have a proper inflammatory response,” he said.

He plans to continue his research, including testing that hypothesis.

About this neuroscience research article

Funding: The work was supported by the National Institutes of Health, grants R01 NS083542, R21 NS101281 and T32 GM007055; and the Owens Family Foundation.

Source: Josh Barney – University of Virginia Health System
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis” by Dorian A Rosen, Scott M. Seki, Anthony Fernández-Castañeda, Rebecca M. Beiter, Jacob D. Eccles, Judith A. Woodfolk and Alban Gaultier in Science Translational Medicine. Published February 6 2019.
doi:10.1126/scitranslmed.aau5266

Cite This NeuroscienceNews.com Article
University of Virginia Health System”Antidepressants Could Stop Deadly Sepsis.” NeuroscienceNews. NeuroscienceNews, 14 February 2019.
<http://neurosciencenews.com/sepsis-antidepressants-10740/>.
University of Virginia Health System(2019, February 14). Antidepressants Could Stop Deadly Sepsis. NeuroscienceNews. Retrieved February 14, 2019 from http://neurosciencenews.com/sepsis-antidepressants-10740/
University of Virginia Health System”Antidepressants Could Stop Deadly Sepsis.” http://neurosciencenews.com/sepsis-antidepressants-10740/ (accessed February 14, 2019).

Abstract

Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis

Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.

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