Enzyme regulation may protect the brain against oxygen deprivation damage
Researchers at Massachusetts General Hospital (MGH), US, have identified an enzyme that may be a potential therapeutic target to protect the brain from oxygen deprivation damage, or hypoxia. Severe hypoxia may cause devastating side effects from a stroke or heart attack due to either tissue or brain damage.
In this study, the researchers set out to investigate the longer-term effects of exposure to hydrogen sulfidegas – a state of “suspended animation” could be induced in mice after inhalation.
The researchers exposed groups of mice to hydrogen sulfide for four hours a day, for five consecutive days. The suspended animation-like state followed, with the animals’ movement slowing and body temperatures dropping.
“But, to our surprise, the mice very quickly became tolerant to the effects of inhaling hydrogen sulfide,” said Dr. Fumito Ichinose, an attending physician at MGH. “By the fifth day, they acted normally and were no longer affected by hydrogen sulfide.”
The mice could also tolerate severe hypoxia: the researchers hypothesised that breathing hydrogen sulfide was boosting levels of enzymes in the brain that metabolise sulfides, which are known to accumulate in the brain during hypoxia. One enzyme, called SQOR, rose markedly in the brains of mice after a few days of breathing the gas.
The researchers then used gene therapy to artificially increase or decrease the levels of SQOR in mice and ground squirrels – the latter of which is a hibernating creature with naturally higher levels of the enzyme that may help it get through long winters with low oxygen.
When the ground squirrels’ SQOR levels were decreased, the damaging effects of hypoxia appeared; while mice that had their levels boosted were better protected in cases of low oxygen. In a step closer to practical applications, the researchers then tested an experimental drug called SS-20, which scavenges excess sulfides in the brain. Mice given this drug were also better protected against hypoxia.
The researchers are now investigating SS-20 and other candidates for use in humans, with the eventual goal of being able to reduce damage from hypoxia caused by events like heart attacks and strokes.
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