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Calming overexcited neurons may protect brain after stroke

By scanning the genomes of nearly 6,000 stroke patients, researchers at Washington University School of Medicine in St. Louis identified two genes associated with recovery. Both are involved in regulating neuronal excitability, suggesting that targeting overstimulated neurons may help promote recovery in the pivotal first 24 hours. (Image: Getty Images)

A new study has prompted scientists to reconsider a once-popular yet controversial idea in stroke research.

Neuroscientists believed that, in the aftermath of a stroke, calming overexcited neurons might prevent them from releasing a toxic molecule that can kill neurons already damaged by lack of oxygen. This idea was supported by studies in cells and animals, but it lost favor in the early 2000s after numerous clinical trials failed to improve outcomes for stroke patients.

But a fresh approach has yielded evidence that the idea may have been discarded too hastily. The new findings are available online in the journal Brain.

By scanning the whole genomes of nearly 6,000 people who had experienced strokes, researchers at Washington University School of Medicine in St. Louis identified two genes associated with recovery within the pivotal first 24 hours after stroke. Events — good or bad — that occur in the first day set stroke patients on their courses toward long-term recovery. Both genes turned out to be involved in regulating neuronal excitability, providing evidence that overstimulated neurons influence stroke outcomes.

“There’s been this lingering question about whether excitotoxicity really matters for stroke recovery in people,” said co-senior author Jin-Moo Lee, MD, PhD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “We can cure stroke in a mouse using blockers of excitotoxicity. But in humans we performed numerous clinical trials, and we couldn’t move the needle. Every last one of them was negative. In this study, out of 20,000 genes, the top two genetic hits point to mechanisms involving neuronal excitation. That’s pretty remarkable. This is the first genetic evidence that shows excitotoxicity matters in people and not just in mice.”

Every year nearly 800,000 people in the U.S. have ischemic strokes, the most common kind of stroke. Ischemic strokes occur when a clot blocks a blood vessel and cuts off oxygen to part of the brain, triggering sudden numbness, weakness, confusion, difficulty speaking or other symptoms. Over the next 24 hours, some people’s symptoms continue to worsen while others’ stabilize or improve.

In the 1990s, Dennis Choi, MD, PhD, then head of the Department of Neurology at Washington University, performed groundbreaking research on excitotoxicity in stroke. He and others showed that stroke can cause neurons to release large amounts of glutamate, a molecule that transmits excitatory messages between neurons. Glutamate is constantly being released by neurons as part of the normal functioning of the nervous system, but too much all at once can be toxic. Efforts to translate this basic research into therapies for people did not pan out, and eventually pharmaceutical companies let their anti-excitotoxic drug development programs lapse.

But Lee, who formerly worked on excitotoxicity with Choi, did not give up. He teamed up with genetics researcher and co-senior author Carlos Cruchaga, PhD, the Barbara Burton and Reuben M. Morriss III Professor of Neurology and a professor of psychiatry; first author Laura Ibañez, PhD, an assistant professor of psychiatry; and co-author Laura Heitsch, MD, an assistant professor of emergency medicine and of neurology, to tackle the question of what drives post-stroke brain injury. The team identified people who had experienced strokes, and they looked for genetic differences between those who naturally recovered substantial function in the first day and those who did not.

Read more on WUSM News.