January 8, 2018Neurology
An ischemic stroke occurs when a clot cuts off blood flow to part of the brain, depriving those cells of oxygen and nutrients like the blood sugar glucose that they need to survive. Nearly 800,000 Americans experience a stroke every year and 87% of those are ischemic strokes. Currently, the only way to minimize stroke-induced cell death is to remove the clot as soon as possible. A treatment to help brain cells survive a stroke-induced lack of oxygen and glucose could dramatically improve patient outcomes, but no such neuroprotective agents for stroke patients exist.
Now, in the fight against brain damage caused by stroke, hibernating ground squirrels may provide some key insights and answers. While ground squirrel brains experience dramatically reduced blood flow during hibernation, just like human patients after a certain type of stroke, the squirrels emerge from their extended naps suffering no ill effects. Now, according to an article published in The FASEB Journal (16 November 2017), a potential drug has been identified that could grant the same resilience to the brains of ischemic stroke patients by mimicking the cellular changes that protect the brains of ground squirrels. The study found that a cellular process called SUMOylation goes into overdrive in a certain species of ground squirrel during hibernation. The authors suspected this was how the animals' brains survived the reduced blood flow caused by hibernation, and subsequent experiments in cells and mice confirmed this hypothesis.
SUMOylation occurs when an enzyme attaches a molecular tag called a Small Ubiquitin-like Modifier (SUMO) to a protein, altering its activity and location in the cell. Other enzymes called SUMO-specific proteases (SENPs) can then detach those tags, thereby decreasing SUMOylation. In the current study, the authors examined whether any of over 4,000 molecules from the NCATS small molecule collections could boost SUMOylation by blocking a SENP called SENP2, which would theoretically protect cells from a shortage of life-sustaining substances. The authors first used an automated process to examine whether the compounds prevented SENP2 from severing the connection between a tiny metal bead and an artificial SUMO protein. This system, along with computer modeling and further tests performed both in and outside of cells, whittled the thousands of candidate molecules down to eight that could bind to SENP2 in cells and were non-toxic. Two of those - ebselen and 6-thioguanine - were then found to both boost SUMOylation in rat cells and keep them alive in the absence of oxygen and glucose. A final experiment showed that ebselen boosted SUMOylation in the brains of healthy mice more than a control injection. 6-thioguanine was not tested because it is a chemotherapy drug with side effects that make it unsuitable as a potential stroke treatment. The authors now plan to test whether ebselen can protect the brains of animal models of stroke. Because SUMOylation affects a variety of molecules, the authors believe that their approach could inspire similar attempts to treat neurological conditions by targeting pathways with wide-ranging effects.