Calming overexcited neurons may protect brain after stroke
New data prompts reconsideration of decades-old theory about brain injury
due to stroke

Date:
April 21, 2022
Source:
Washington University School of Medicine
Summary:
By scanning the genomes of nearly 6,000 stroke patients, researchers
have 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.



FULL STORY ==========================================================================
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 journalBrain.

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 Iban~ez,
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.

As members of the International Stroke Genetics Consortium, the research
team was able to study 5,876 ischemic 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
over 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 gauges a person's degree of neurological impairment based on measures such as the ability to answer
basic questions such as "How old are you?"; to perform movements such
as holding up the arm or leg; and to feel sensation when touched.

The researchers performed a genomewide association study by scanning the participants' DNA for genetic variations related to the change in their
NIH stroke scale scores. The top two hits were genes that coded for
the proteins ADAM23 and GluR1. Both are related to sending excitatory
messages between neurons. ADAM23 forms bridges between two neurons so
that signaling molecules such as glutamate can be passed from one to
the other. GluR1 is a receptor for glutamate.

"We started with no hypotheses about the mechanism of neuronal injury," Cruchaga said. "We started with the assumption that some genetic variants
are associated with stroke recovery, but which ones they are, we did not
guess. We tested every single gene and genetic region. So the fact that
an unbiased analysis yielded two genes involved in excitotoxicity tells
us that it must be important." In the years since anti-excitotoxic drug development was abandoned, clot- busting drugs have become the standard
of care for ischemic stroke. Such drugs aim to restore blood flow so that oxygen -- and anything else in the bloodstream, including medication --
can reach affected brain tissue.

Consequently, experimental neuroprotective therapies that failed in
the past might be more effective now that they have a better chance of
reaching the affected area.

"We know that that first 24-hour period has the greatest impact on
outcomes," Lee said. "Beyond 24 hours, there's diminishing returns in
terms of influence on long-term recovery. Right now, we don't have any neuroprotective agents for that first 24 hours. Many of the original
studies with anti-excitotoxic agents were performed at a time when we
weren't sure about the best trial design.

We've learned a lot about stroke in the last few decades. I think it's
time for a re-examination."

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Laura Ibanez, Laura Heitsch, Caty Carrera, Fabiana H. G. Farias,
Jorge L.

Del Aguila, Rajat Dhar, John Budde, Kristy Bergmann, Joseph
Bradley, Oscar Harari, Chia-Ling Phuah, Robin Lemmens, Alessandro
A. Viana Oliveira Souza, Francisco Moniche, Antonio Cabezas-Juan,
Juan Francisco Arenillas, Jerzy Krupinksi, Natalia Cullell,
Nuria Torres-Aguila, Elena Muin~o, Jara Ca'rcel-Ma'rquez, Joan
Marti-Fabregas, Raquel Delgado- Mederos, Rebeca Marin-Bueno,
Alejandro Hornick, Cristofol Vives-Bauza, Rosa Diaz Navarro,
Silvia Tur, Carmen Jimenez, Victor Obach, Tomas Segura, Gemma
Serrano-Heras, Jong-Won Chung, Jaume Roquer, Carol Soriano-
Tarraga, Eva Giralt-Steinhauer, Marina Mola-Caminal, Joanna Pera,
Katarzyna Lapicka-Bodzioch, Justyna Derbisz, Antoni Davalos, Elena
Lopez- Cancio, Lucia Mun~oz, Turgut Tatlisumak, Carlos Molina, Marc
Ribo, Alejandro Bustamante, Tomas Sobrino, Jose Castillo-Sanchez,
Francisco Campos, Emilio Rodriguez-Castro, Susana Arias-Rivas,
Manuel Rodri'guez- Ya'n~ez, Christina Herbosa, Andria L. Ford,
Alonso Gutierrez-Romero, Rodrigo Uribe-Pacheco, Antonio Arauz,
Iscia Lopes-Cendes, Theodore Lowenkopf, Miguel A. Barboza, Hajar
Amini, Boryana Stamova, Bradley P.

Ander, Frank R Sharp, Gyeong Moon Kim, Oh Young Bang, Jordi Jimenez-
Conde, Agnieszka Slowik, Daniel Stribian, Ellen A. Tsai, Linda
C. Burkly, Joan Montaner, Israel Fernandez-Cadenas, Jin-Moo Lee,
Carlos Cruchaga.

Multi-ancestry GWAS reveals excitotoxicity associated with outcome
after ischaemic stroke. Brain, 2022; DOI: 10.1093/brain/awac080 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220421181207.htm

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