By studying ground squirrels’ unique ability to awaken from hibernation without any negative side effects from reduced blood flow to the brain, researchers have identified a small molecule that could protect against stroke-induced brain damage in humans. Ischemic strokes, which are caused by blood clots that blocks blood flow to the brain, make up eighty-seven percent of the almost 800,000 strokes in America every year. The research was presented recently in the FASEB Journal. Since the only current treatment for strokes is to physically remove the blood clot as soon as possible, a new treatment to quickly protect brain cells from damage would be a significant advancement in stoke therapy.
"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," said Francesca Bosetti, Ph.D., Pharm.D., program director at the NIH's National Institute of Neurological Disorders and Stroke (NINDS).
SUMOylation is a post-translational modification widespread in some types of hibernating ground squirrels and previous experiments have shown that it is what protects protein brain cells from damage during long periods of low blood flow. During the process, an enzyme attaches a small ubiquitin-like modifier (SUMO) molecule to a protein changing that protein’s activity and location. SUMOylation is reduced by cleavage of the tag by SUMO-specific proteases (SENPs).
The research team used quantitative high throughput screening of 4,000 molecules in addition to computer modeling and other tests to identify two compounds that inhibited SENP2, therefore, increasing SUMOylation. One of the molecules, ebselen, was further tested to show that it boosted SUMOylation in the brains of healthy mice over the control group. The next step is to test the drug in stroke mouse models.