A new study has prompted scientists to reconsider a once popular but controversial idea in stroke research.
Neuroscientists believe that in the aftermath of a stroke, calming overexcited neurons may prevent them from releasing a toxic molecule that can kill neurons already damaged by a lack of oxygen. This idea was supported by cell and animal studies, but lost popularity in the early 2000s after several clinical trials failed to improve outcomes for stroke patients.
But a new approach yielded evidence that the idea may have been hastily discarded. The new findings are available online in the journal brain.
By scanning the entire genomes of nearly 6,000 people who have had strokes, researchers at Washington University School of Medicine in St. Louis identified two genes linked to recovery within a pivotal 24 hours after a stroke. The events — good or bad — that occur on the first day set stroke patients on their cycle toward long-term recovery. Both genes have been shown to have a role in regulating neuronal excitability, providing evidence that overstimulated neurons influence stroke outcomes.
Co-lead author Jin-Moo Lee, MD, PhD, and Professor Andrew B. Gretchen B. Jones, chief of neurology, said: “There has been this longstanding question about whether excitatory toxicity is really important for stroke recovery in people.” “We can treat stroke in a mouse with excitatory toxicity blockers. But in humans we’ve run several clinical trials, and we haven’t been able to move the needle. Each one was negative. In this study, out of 20,000 genes, the top two were genetic findings suggesting This is the first genetic evidence to show the importance of excitatory toxicity in humans and not just in mice.”
Each year, approximately 800,000 people in the United States have ischemic strokes, the most common type of stroke. Ischemic strokes occur when a clot blocks a blood vessel and cuts off oxygen to part of the brain, resulting in sudden numbness, weakness, confusion, difficulty speaking, or other symptoms. Over the next 24 hours, some people’s symptoms continue to get worse while others stabilize or improve.
In the 1990s, Dennis Choi, MD, PhD, then chair of the Department of Neurology at the University of Washington, conducted pioneering research on stroke toxicity. He and others showed that a stroke can cause neurons to release large amounts of glutamate, a molecule that transmits excitatory messages between neurons. Glutamate is constantly released by neurons as part of the normal functioning of the nervous system, but excessive use of it once can be toxic. Efforts to translate this basic research into treatments for people were unsuccessful, and drug companies eventually let antivenom drug development programs fizzle out.
But Li, who had previously worked on toxicity with Choi, didn’t give up. Collaborated with genetics researcher and co-author Carlos Kruchaga, Ph.D., Professor of Neurology Barbara Burton and Robin M. Morris III, Professor of Psychiatry; first author Laura Ibanez, Ph.D., assistant professor of psychiatry; and co-author Laura Heitsch, MD, assistant professor of emergency medicine and neurology, to address the question of what drives brain injury after stroke. The team identified people who had experienced strokes, and looked for genetic differences between those who regained function normally on the first day and those who did not.
As members of the International Consortium of Stroke Genetics, the research team was able to study 5,876 stroke patients from seven countries: Spain, Finland, Poland, the United States, Costa Rica, Mexico and South Korea. They measured each person’s recovery or deterioration during the first day using the difference between their scores on the National Institutes of Health (NIH) stroke scale at six and 24 hours after symptoms first appeared. The scale measures a person’s neurotic impairment based on measures such as the ability to answer basic questions such as “How old are you?” to perform movements such as raising an arm or a leg; And feel the sensation when you touch it.
The researchers conducted a genome-wide association study by scanning participants’ DNA for genetic differences related to change in the National Institutes of Health’s Stroke Scale scores. The two most important findings were the genes coding for the ADAM23 and GluR1 proteins. Both are associated with sending excitatory messages between neurons. ADAM23 forms bridges between two neurons so that signaling molecules such as glutamate can travel from one to the other. GluR1 is a glutamate receptor.
“We started without hypotheses about the mechanism of neuronal injury,” Kroshaga said. “We started with the assumption that some genetic variants were associated with stroke recovery, but we didn’t guess which ones. We tested every single gene and genetic region. So the fact that the unbiased analysis yielded two genes implicated in excitatory toxicity tells us that it should be important.”
In the years since antivenom drug development was abandoned, clot-busting drugs have become the standard of care for ischemic stroke. These medications aim to restore blood flow so that oxygen — and anything else in the bloodstream, including medications — can reach the affected brain tissue. Thus, experimental neuroprotective treatments that failed in the past may be more effective now that they have a better chance of reaching the affected area.
“We know that this first 24 hour period has the greatest impact on results,” Lee told me. “After 24 hours, there are diminishing returns in terms of impact on long-term recovery. Currently, we do not have any neuroprotective agents during those first 24 hours. Many of the original studies were done with antitoxin agents simultaneously. We’re sure of the best trial design. We’ve learned a lot about stroke in the past few decades. I think it’s time for a re-examination.”