The serendipitous discovery of H₂S-induced hypoxia in the brain paves the way for possible therapies for ischemic stroke.
Strokes are of two types: Hemorrhagic and Ischemic. Hemorrhagic strokes occur due to excessive bleeding. Lesser blood supply to the brain causes hypoxia (oxygen deprivation) which leads to an ischemic stroke. Hypoxia can bring about metabolic imbalance and brain tissue damage. In some cases, the arteries that supply blood to the brain can narrow (intracranial artery stenosis) and allow for plaque formation, causing a stroke. In other cases, prolonged exposure to certain gases such as Hydrogen Sulphide (H₂S) can also cause hypoxia.
Scientists at Massachusetts General Hospital had initially planned to develop techniques to induce suspended animation. Suspended animation is a condition where human functions can be temporarily halted and “reawakened” after some time (similar to hibernation). The scientists induced suspended animation in mice by exposing them to H₂S (“sewer gas”). Safely inducing suspended animation can have medical uses such as halting the function of a terminal patient until a cure is found. The mice remained in that state for four days and surprisingly, started acting normally by the fifth day. This led the scientists to believe that the mice had become resistant to hydrogen sulphide exposure.
These mice who tolerated the H2S exposure were also protected from hypoxia. The scientists then discovered that an enzyme called Sulphide:Quinone Oxidoreductase (SQOR) was responsible for H₂S metabolism that protected the mice from cerebral hypoxia. The results of the study were published in Nature Communications. They also formulated a drug that scavenges excess sulphides from the brain which can be a possible treatment for ischemic strokes.
The mechanism of hypoxia is not completely understood. The brain having limited glycolytic capacity relies on the mitochondria for ATP production by the process of oxidative phosphorylation. Lower supply of O₂ to the brain can elevate sulphide levels which goes on to inhibit cytochrome C-oxidase, an enzyme involved in oxidative phosphorylation. This can impair ATP production and cause membrane depolarization leading to irreversible neuronal damage. Sulphides can also bring about the formation of Nitric Oxide and Reactive Oxygen Species which are extremely toxic to the neurons. Hence, sulphides cause bioenergetic failure which leads to ischemic brain injury.
These sulphides are metabolised by the SQOR enzyme. SQOR oxidises the sulphides to persulphides and donates the electrons to the oxidative phosphorylation process. Thus enabling ATP production and maintaining mitochondrial energy homeostasis. The level of SQOR is more in the liver, skeletal muscles, heart and lungs than in the brain. Hence the impaired functioning of SQOR makes the brain more susceptible to sulphide poisoning. A mutation in the gene that codes for the SQOR enzyme leads to a rare but deadly neurological condition called Leigh’s Syndrome that usually leads to early death.
Through this study, the researchers uncovered the role of sulphide metabolism in strokes. The lesser the SQOR enzyme in the brain, the more sensitive the mice is to hypoxia. They also observed that intermittent exposure to H₂S gas enhanced the function of SQOR, therefore protecting the mice from hypoxia. The scientists even explained the sexual dimorphism observed with the occurrence of stroke. The female mice were more resistant to hypoxia than males. Estrogen enables the higher expression of SQOR. This resistance is lost when the ovary was removed in the mice and can be reversed when supplemented with estrogen.
Several mammals have varying resistance levels to hypoxia due to the varying levels of SQOR. Line Ground Squirrels (underground hibernating rodents) have 100 fold more SQOR levels than mice and rats, making them resistant to hypoxia. The scientists went on to construct an SS-20 drug that scavenged excess sulphides and improved the neurological functions in mice within 48 hours of treatment. Treatment with hydroxocobalamin aka Vitamin B12 was also able to remove sulphide particles and reduce the intensity of ischemic stroke in the mice.
This study portrays the crucial role of sulphide metabolism in causing ischemic stroke. The scientists also plan to study other conditions caused by sulphide accumulation such as Leigh’s syndrome. This study proposes accelerating sulphide catabolism or sulphide scavenging drugs as possible treatments for ischemic strokes for treating ischemic strokes. “For some patients, treatment with a sulfide scavenger might be lifesaving,” assert the researchers.