Surprising discovery could lead to new treatments for stroke and cardiac arrest

Researchers identify a mechanism that could lead to new treatments for brain damage caused by oxygen deprivation.

In a surprising discovery, researchers at Massachusetts General Hospital (MGH) have identified a mechanism that protects the brain from the effects of hypoxia, a potentially fatal oxygen deprivation. This fortuitous discovery, which they report in Nature Communication, could help in the development of therapies for stroke, as well as brain damage that can result from cardiac arrest, among other conditions.

However, this study began with a very different goal, says lead author Fumito Ichinose, MD, PhD, attending physician in the Department of Anesthesia, Critical Care and Pain Medicine at the MGH and principal investigator at the Center. anesthesia for intensive care research. One area of ​​interest for Ichinose and his team is to develop techniques to induce suspended animation, that is to say to temporarily put the vital functions of a human on the back burner, with the possibility of “waking them up” later. . This state of being would be similar to what bears and other animals experience during hibernation. Ichinose believes the ability to safely induce suspended animation could have valuable medical applications, such as pausing the life processes of a patient with an incurable disease until effective therapy is available. found. It could also allow humans to travel long distances in space (which has often been described in science fiction).

A 2005 study found that inhaling a gas called hydrogen sulfide caused mice to enter a state of suspended animation. Hydrogen sulfide, which smells like rotten eggs, is sometimes called “sewage gas”. Deprivation of oxygen in the brain of a mammal results in increased production of hydrogen sulfide. As this gas accumulates in the tissues, hydrogen sulfide can stop energy metabolism in neurons and cause their death. Oxygen deprivation is a hallmark of ischemic stroke, the most common type of stroke, and other brain damage.

In the Nature Communication study, Ichinose and his team initially set out to find out what happens when mice are exposed to hydrogen sulfide repeatedly, over an extended period of time. At first, the mice entered a state similar to suspended animation – their body temperature dropped and they were motionless. “But, to our surprise, the mice very quickly became tolerant to the effects of inhaling hydrogen sulfide,” Ichinose explains. “By the fifth day, they were acting normally and were no longer affected by the hydrogen sulfide.”

Interestingly, the mice that became tolerant to hydrogen sulfide were also able to tolerate severe hypoxia. What protected these mice from hypoxia? The Ichinosis group suspected that enzymes in the brain that metabolize sulfide could be responsible. They found that levels of an enzyme, called sulfide: quinone oxidoreductase (SQOR), increased in the brains of mice when they breathed in hydrogen sulfide for several days in a row. They hypothesized that SQOR plays a role in resistance to hypoxia.

There was strong evidence for this hypothesis in nature. For example, female mammals are known to be more resistant than males to the effects of hypoxia – and the former have higher levels of SQOR. When SQOR levels are artificially reduced in women, they become more vulnerable to hypoxia. (Estrogen may be responsible for the observed increase in SQOR, as protection against the damaging effects of hypoxia is lost when the estrogen-producing ovaries of a female mammal are removed.) Additionally, some hibernating animals, like the striped ground squirrel, are very tolerant of hypoxia, which allows them to survive while their body’s metabolism slows down during the winter. The brain of a typical ground squirrel has 100 times more SQOR than that of a rat of similar size. However, when Ichinose and his colleagues “turned off” the expression of SQOR in the brains of squirrels, their protection against the effects of hypoxia was lost.

Meanwhile, when Ichinose and his colleagues artificially increased SQOR levels in the brains of mice, “they developed a robust defense against hypoxia,” Ichinose explains. His team increased the level of SQOR using gene therapy, a technically complex and impractical approach at this point. On the other hand, Ichinose and his colleagues have shown that “scavenging” sulfide, using an experimental drug called SS-20, reduced gas levels, thus sparing the brains of mice when they were starved of oxygen.

The human brain has very low levels of SQOR, which means that even a modest buildup of hydrogen sulfide can be harmful, Ichinose explains. “We hope that one day we will have drugs that could work like SQOR in the body,” he says, noting that his lab is studying SS-20 and several other candidates. Such drugs could be used to treat ischemic strokes, as well as patients who have suffered cardiac arrest, which can lead to hypoxia. Ichinose’s lab is also studying how hydrogen sulfide affects other parts of the body. For example, hydrogen sulfide is known to build up in other conditions, such as certain types of Leigh syndrome, a rare but serious neurological disorder that usually results in premature death. “For some patients,” Ichinose explains, “treatment with a sulfide scavenger can save lives”.

Reference: “Sulphide Catabolism Improves Hypoxic Brain Injury” by Eizo Marutani, Masanobu Morita, Shuichi Hirai, Shinichi Kai, Robert MH Grange, Yusuke Miyazaki, Fumiaki Nagashima, Lisa Traeger, Aurora Magliocca, Tomoaki Ida, Tetsuro Matsunaga, Daniel R . Flicker, Benjamin Corman, Naohiro Mori, Yumiko Yamazaki, Annabelle Batten, Rebecca Li, Tomohiro Tanaka, Takamitsu Ikeda, Akito Nakagawa, Dmitriy N. Atochin, Hideshi Ihara, Benjamin A. Olenchock, Xinggui Shen, Motohiro Nishoka, Christopher G. Kevil, Ming Xian, Donald B. Bloch, Takaaki Akaike, Allyson G. Hindle, Hozumi Motohashi and Fumito Ichinose, May 25, 2021, Nature Communication.
DOI: 10.1038 / s41467-021-23363-x

The lead author of the study is Eizo Marutani, MD, a researcher in the Department of Critical Care Anesthesia and Pain Medicine at the MGH and an instructor at Harvard Medical School (HMS). Ichinose is also the William Thomas Green Morton Professor of Anesthesia at HMS.

This study was funded by grants from the Japanese Ministry of Education, Science, Sports and Technology; Japan Science and Technology Agency; Japan Agency for Medical Research and Development; the National Institute of Neurological Disorders and Stroke; National Institute of Heart, Lungs and Blood; the National Institute of General Medical Sciences; and the National Science Foundation.