Recently published in The FASEB Journal, the study describes a cellular process in the brains of ground squirrels that enables their brain cells to survive a reduction in blood flow during hibernation.
This information led the researchers to discover a compound that could trigger this process in humans, bringing us closer to a new drug for ischemic stroke – the most common form of the condition.
An ischemic stroke occurs when the flow of oxygen-rich blood to the brain is blocked, most commonly due to a blood clot. This blockage prevents brain cells from getting the oxygen and nutrients they need, and they can die as a result.
It is this brain cell death that leads to the disabilities often seen with stroke, such as impaired speech and paralysis on one side of the body.
In order to limit the brain damage caused by ischemic stroke, blood flow must quickly be restored to the brain. A drug called tissue plasminogen activator (tPA) is the first-line treatment for ischemic stroke, which works by dissolving blood clots.
However, this medication must be given to patients within 3 hours of their first ischemic stroke symptoms, and some individuals with other medical conditions — such as bleeding disorders — may not be eligible for tPA treatment.
As such, there is a desperate need for new therapies that can protect brain cells against ischemic stroke. Could ground squirrels help to reach this goal?
Ground squirrels, SUMOylation, and stroke
Living up to their name, ground squirrels are rodents that live in burrows, and they are commonplace in parks and gardens across the U.S.
During the winter months, the majority of ground squirrels hibernate. In previous research, Dr. John Hellenbeck — of the National Institute of Neurological Disorders and Stroke (NINDS) — found that during hibernation, ground squirrels experience an increase in SUMOylation.
Through experiments in rats and mice, Dr. Hellenbeck and colleagues found that SUMOylation helps to maintain brain cell function during exposure to adverse conditions during hibernation, such as reduced blood flow.
SUMOylation is a cellular process in which a Small Ubiquitin-like Modifier (SUMO) binds to a protein in a cell. This changes the activity of the protein, as well as its placement within the cell.
The researchers explain that there are enzymes called SUMO-specific proteases (SENPs) that prevent SUMO from attaching to proteins, which leads to a reduction in SUMOylation.
For the new study, Dr. Hellenbeck and his team set out to identify molecules that could block a particular SENP, called SENP2. Their theory was that inhibiting this enzyme might prompt an increase in SUMOylation, which could protect brain cells against the damage caused by reduced blood flow, just like it does in ground squirrels.
"If we could only turn on the process hibernators appear to use to protect their brains, we could help protect the brain during a stroke and ultimately help people recover," says first study author Joshua Bernstock, who is a graduate student in Dr. Hellenbeck's lab at NINDS.
Compound protected brain cells in mice
For their study, the researchers sifted through more than 4,000 molecules within the small molecules collection held by the National Institute of Health's (NIH) National Center for Advancing Translational Sciences (NCATS).
Through computer modeling and cellular experiments, the researchers identified eight molecules that were able to bind to SENP2 and inhibit its activity.
On further experiments in rat cells, the researchers found that two of these compounds — ebselen and 6-thioguanine — led to an increase in SUMOylation, and they were able to protect the cells when they were deprived of oxygen and glucose.
In mouse models, the team found that ebselen led to a greater rise in SUMOylation in the rodents' brains than a control injection.
The researchers note that 6-thioguanine is a chemotherapy drug with side effects that make it unsuitable as a treatment for stroke, so they did not test the molecule in mouse models.
Still, the team plans to test ebselen further, with the hope that it could lead to an effective strategy to prevent brain damage caused by ischemic stroke.
"For decades scientists have been searching for an effective brain-protecting stroke therapy to no avail. If the compound identified in this study successfully reduces tissue death and improves recovery in further experiments, it could lead to new approaches for preserving brain cells after an ischemic stroke."
Francesca Bosetti, Ph.D., program director at NINDS
Thanks to those cute little squirrels that populate our backyards, we may be one step closer to a new treatment for one of the most debilitating conditions in America.