Hypoxia is a potentially lethal deprivation of oxygen. The brain is the most sensitive organ to hypoxia. Now, researchers at Massachusetts General Hospital (MGH) identified a mechanism that protects the brain from the effects of hypoxia.

Their findings are published in the journal Nature Communications in a paper titled, “Sulfide catabolism ameliorates hypoxic brain injury.”

Their findings could lead to the development of therapies for strokes, as well as brain injury that can result from cardiac arrest.

“The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood,” wrote the researchers. “Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide: quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide.”

The study began with a different objective, explained senior author Fumito Ichinose, MD, PhD, an attending physician in the department of anesthesia, critical care, and pain medicine at MGH, and principal investigator in the Anesthesia Center for Critical Care Research. One area of focus for Ichinose and his team is developing techniques for inducing suspended animation, that is, putting a human’s vital functions on temporary hold, with the ability to “reawaken” them later. Ichinose believes that 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 an effective therapy is found.

Oxygen deprivation in a mammal’s brain leads to increased production of hydrogen sulfide, which can halt energy metabolism in neurons and cause them to die. The researchers initially set out to learn what happens when mice are exposed to hydrogen sulfide repeatedly, over an extended period. The mice entered a suspended-animation-like state.

“But, to our surprise, the mice very quickly became tolerant to the effects of inhaling hydrogen sulfide,” stated Ichinose. “By the fifth day, they acted normally and were no longer affected by hydrogen sulfide.”

The mice that became tolerant to hydrogen sulfide were also able to tolerate severe hypoxia. The researchers suspected that enzymes in the brain that metabolize sulfide might be responsible, and discovered that levels of an enzyme, called sulfide:quinone oxidoreductase (SQOR), rose in the brains of mice when they breathed hydrogen sulfide several days in a row.

The researchers artificially increased SQOR levels in the brains of mice using gene therapy.

“Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury,” wrote the researchers. “Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury,” concluded the researchers.

The researchers hope that there will one day be drugs that could work like SQOR in the body. Ichinose’s lab is studying the drug SS-20 and several other candidates. These potential treatments could one day be used to treat ischemic strokes, as well as patients who have suffered cardiac arrest, which can lead to hypoxia.

The researchers are also investigating how hydrogen sulfide affects other parts of the body. “For some patients,” said Ichinose, “treatment with a sulfide scavenger might be lifesaving.”

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