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Triggering stroke recovery
LOS ANGELES—As an M.D./Ph.D. student, Dr. S. Thomas Carmichael wanted to understand how the brain repairs itself and recovers, and why some people get better after a stroke. As Carmichael, a professor and vice chair for research and programs in the University of California, Los Angeles (UCLA) department of neurology, said in an article in Nature Neuroscience, “Stroke is the leading cause of adult disability because of the brain’s limited capacity for repair.”
In fact, stroke kills nearly 130,000 Americans each year, one of every 20 deaths in the United States, according to the U.S. Centers for Disease Control and Prevention. Every year, more than 795,000 people in the country have a stroke, about 610,000 of them for the first time. Stroke costs the nation an estimated $34 billion each year, including the cost of healthcare, medications and missed days of work.
Carmichael and his colleagues at UCLA, where he has been since 1998, wanted to know what neurons grow after a stroke or injury to the brain, identify drug targets based on gene expression during recovery and understand “what turns on the trigger for recovery.” They learned that growth differentiation factor 10 (GDF10) is a stroke-induced signal for axonal sprouting and functional recovery in multiple species. After a stroke, the GDF10 molecule signals brain tissue to form new connections to compensate for the damage and initiate repairs to the brain.
According to Carmichael, “The brain has a limited capacity for recovery after stroke. “Most stroke patients get better after their initial stroke, but few fully recover. If the signals that lead to this limited recovery after stroke can be identified and turned into a treatment, then it might be possible to enhance brain repair after stroke.”
In a five-year study, the researchers discovered that GDF10 upregulation after stroke was applicable to mice, nonhuman primates and humans and exhibited the same patterns of action. After discovering that GDF10 enhances brain cells’ ability to form new connections, the scientists identified the signaling systems that control the process. They learned that GDF10 promotes new connections to form in the brain after stroke, thus mediating the recovery of the ability to control bodily movement. GDF10 promoted axonal sprouting through TGF beta receptors and improved motor recovery after stroke.
Finally, the team identified all of the molecules that are turned on or off by GDF10 in brain cells after a stroke and compared the cells’ RNA to RNA in comparable cells during brain development and normal learning—as well as to RNA in the brain cells of people with other diseases. Using RNA sequencing, the researchers found that GDF10 regulates several molecular signaling systems to induce a neuronal growth state that is distinct from other developmental, CNS-injury and adult plasticity phenotypes.
The researchers determined that GDF10 regulates a unique collection of molecules to improve recovery after stroke. The discovery indicates that brain tissue regenerating after a stroke is a unique process rather than just a reactivation of the molecules that are active in brain development, according to Carmichael.
In addition, the research team administered GDF10 to animals that had experienced strokes and then mapped the connections in the brain that are tied to body movement. They compared those to the connections in animals who had experienced a stroke but were not given GDF10, in animals with healthy brains and with animals that had experienced a stroke and had a reduced level of GDF10.
“The results indicated that GDF10 normally is responsible for the very limited process of the formation of new connections after stroke,” Carmichael says. “Delivering more GDF10 markedly enhances the formation of new connections and does so mostly in a specific brain circuit. The formation of connections in this circuit with GDF10 administration significantly enhanced recovery of limb control after stroke.”
In the future, Carmichael and his team hope to identify a small molecule that activates the GDF10 signaling systems and that could eventually lead to the development of a drug to enhance recovery from strokes. They hope to test the molecule on a human candidate in a clinical trial. “We want to demonstrate its potential as a therapeutic target after stroke,” Carmichael concludes.