Drugs that switch your brain into squirrel-mode may save you from a stroke

Hibernation and strokes affect brains similarly—and squirrels have cracked that nut.

In the latest cache of data, researchers dug up a drug that can essentially flip a hibernation switch in brain cells, mimicking conditions in the noggins of dormant squirrels and potentially cushioning the blow from strokes and other cardiovascular incidents. In early tests, the drug protected cells in lab from oxygen and glucose depletion—cell-killing conditions during strokes and hibernation. The drug could also activate those protective hibernation conditions in the brains of live, non-hibernating mice.

The drug development is in its earliest phases—many, many years will have to pass before it finds its way into a clinic, if it even makes it that far (most early drug candidates don’t). But, this latest research follows years of fundamental work on making our brains act more like that of a hibernating squirrel in dire situations. And researchers are still bright-eyed and bushy-tailed about the approach.

“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.” That’s according to a statement from Joshua Bernstock, the first author of the new study and a researcher at the National Institute of Neurological Disorders and Stroke (NINDS). He and his colleagues published their latest results recently in the FASEB Journal.

The researchers note that current treatments for strokes are rather lousy, even though strokes are a common health problem. Nearly 800,000 Americans suffer strokes each year. Most of those are ischemic strokes, which cut back the blood supply to the brain, causing brain damage and cell death that can lead to sensory, motor, and cognitive impairments. Experimental treatments that try to protect brain cells during such a stroke have largely flopped. The main treatment is still only to try to remove clots that are blocking blood flow as soon as possible.

In 2007, the same research group dug up a reason to study brain conditions in hibernating squirrels. The work, led by Dr. John Hallenbeck at NINDS, revealed that a massive molecular system is activated during hibernation in 13-lined ground squirrels (Ictidomys tridecemlineatus). (Common tree squirrels don’t hibernate, in case you were wondering).

The system, dubbed SUMOylation, uses enzymes to tack small ubiquitin-like modifiers (SUMOs) onto proteins in cells. The SUMO tags alter the proteins’ locations and activities in the cells, leading to large-scale changes in molecular signaling systems, gene activity, and DNA repair. Subsequent work found that SUMOylation could protect cells from low oxygen and glucose levels—a scenario that arises during hibernation and strokes. And boosting the system in genetically engineered mice made the mice resistant to damage caused by a depleted blood supply.

Hallenbeck and his colleagues have since been on the hunt for drugs to manipulate the system. If a drug can crank up SUMOylation in human brain cells during a stroke—effectively switching them into a torpor—it could prevent brain damage until blood flow is restored, they hypothesized. In the new study, the researchers found just such a drug.

To find it, the researchers first noted that they could boost SUMOylation by blocking enzymes called SENPs, which actively remove SUMOs from proteins. In other words, with SENPs out of the picture, more proteins keep their SUMOs, and SUMOylation increases overall. To find SENP blockers, they invented a crafty trap: basically, a SUMO-tagged protein would glow when intact. If a SENP comes along and cuts the SUMO, the glow is gone. But, if a drug-SENP combo doesn’t snuff the SUMO glow, that suggests the drug blocked the SENP.

The researchers sifted through more than 4,000 different candidate drug compounds. In the end, they found one compound that blocked SENPs, protected brain cells from oxygen and glucose depletion, and activated SUMOylation in mice. That compound, called ebselen, is set for more experiments to see if it—or an enhanced version of it—can protect animals from stroke damage.

“It is our hope that this finding will ultimately lead to advanced treatments for patients who have ischemic brain damage,” the researchers conclude.

The FASEB Journal, 2017. DOI: 10.1096/fj.201700711R  (About DOIs).

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