New approach points to potential treatment for stroke

Stanford University School of Medicine neuroscientists have demonstrated, in a study published online in Stroke, that a compound mimicking a key activity of a hefty, brain-based protein is capable of increasing the generation of new nerve cells, or neurons, in the brains of mice that have had strokes. The mice also exhibited a speedier recovery of their athletic ability. These results are promising, because the compound wasn't administered to the animals until a full three days after they had suffered strokes, said the study's senior author, Marion Buckwalter, MD, PhD, an assistant professor of neurology and neurological sciences. This means that the compound works not by limiting a stroke's initial damage to the brain, but by enhancing recovery. This is of critical significance, said Buckwalter, a practicing clinical neurologist who often treats recently arrived stroke patients in Stanford Hospital's intensive care unit. "No existing therapeutic agents today enhance recovery from stroke," Buckwalter said. "The only approved stroke drug, tissue plasminogen activator, can bust up clots that initially caused the stroke but does nothing to stimulate the restoration of brain function later." Furthermore, to be effective, tPA has to be given within four and a half hours after a stroke has occurred, she added. "In real life, many people don't get to the hospital that quickly. They may live alone or have their stroke while sleeping, or they and the people close to them didn't recognize the stroke's symptoms well enough to realize they'd just had one." Looking for an alternative, Buckwalter chose to focus on a compound called LM22A-4, which had shown promise in previous research. LM22A-4 is a small molecule whose bulk is less than one-seventieth that of the brain protein it mimics: brain-derived neurotrophic factor, a powerful and long-studied nerve growth factor. BDNF is critical during the development of the nervous system and known to be involved in important brain functions including memory and learning. Stem-cell therapy, while an exciting prospect, is a relatively invasive and expensive way to replace lost or damaged tissue. A drug that could achieve similar results in such a delicate and complex organ as the brain would be a welcome development. "This small molecule stimulates the brain's own stem cells to form new neurons and therefore may be achieving many of the same things a stem-cell transplant would achieve, albeit with a less spectacular technology," said Frank Longo, MD, PhD, professor and chair of neurology and neurological sciences and a co-author of the study. "It represents an entirely new approach for treating conditions for which we have nothing now." Longo, who is the George E. and Lucy Becker Professor in Medicine, and his laboratory colleagues identified LM22A-4 as a potential BDNF mimic in 2011, in collaboration with neurologist Stephen Massa, MD, PhD, at the University of California-San Francisco. (Massa is also listed as a study co-author.)