By altering the balance between neuronal excitation and inhibition, researchers have reduced cell death and improved outcomes in animal models of stroke.

The team published its results in the April 20, 2022, issue of Science Translational Medicine.

Stroke, which occurs when brain cells die following a disruption in the blood supply to the brain, is among the top 10 causes of death, and a leading cause of disability.

But "we've had no new therapies since we put rTPA in the clinic" in the 1990s, Johannes Vogt told BioWorld Science.

And rTPA, whose generic name is alteplase, is tricky to use. It works by busting the clots that are the cause of nearly 90% of strokes, the ischemic strokes.

The other 10%, though, are hemorrhagic strokes, caused by bleeding into the brain due to a vessel rupture. In these strokes, clotting is a major defense mechanism, and treatment with clot busters will make things worse.

It takes imaging to see whether a stroke is hemorrhagic or ischemic, which in turn makes alteplase's time window – the drug needs to be administered within a few hours of a stroke's occurrence – a taller obstacle. A fraction of patients who could benefit from alteplase are not treated with the drug because they cannot be imagined in time.

The work now published by Vogt, who is a professor of medicine at the University of Cologne and co-corresponding author of the paper, focuses on the functional consequences that the loss of blood flow entails. And one of the consequences of neuronal death at the center of the stroke area is excitotoxicity, or the death of further neurons due to excessive activation.

"The stroke core is the part where the brain is damaged, and this is irreversible," Vogt explained. But surrounding the core is what is called the penumbra, an area "where function is altered, but cells can potentially survive. What we do in neurology is to try to save this penumbra."

In previous studies, Vogt and his colleagues have shown that bioactive lipids, and specifically, lysophosphatidic acid (LPA), regulate excitation. However, targeting such lipids is not easy. LPA precursor molecules are produced in the liver and cross the blood-brain barrier, where LPA is then made. Once produced, LPA regulates glutamate release at synapses.

In the work now published in Science Translational Medicine, Vogt, his co-senior authors Frauke Zipp and Robert Nitsch, and their teams first showed that LPA levels were regulated by the enzyme autotaxin, which was produced and secreted by astrocytes.

In animal models, treatment with an autotaxin inhibitor (PF-8380) improved outcomes after experimentally induced stroke. The team also showed that in stroke patients, cerebrospinal fluid levels of autotaxin correlated with stroke severity. Patients with a genetic variant that increased LPA levels also had worse outcomes, as did transgenic mice with the same variant.

The investigators are now developing an autotaxin inhibitor that they want to take into clinical trials.

Vogt said that he would expect the therapeutic approach to be equally applicable to hemorrhagic and ischemic stroke. He cautioned that so far, the team has data only for ischemic stroke.

But "we do not affect blood flow... So the expectation is that we would not harm the hemorrhagic stroke patients," he said.

Beyond the specifics of autotaxin and stroke, the team has described a new mechanism to regulate the balance between excitation and inhibition – a balance that is fundamental to brain function.

"Stroke is the main header, because there is really a clear need for this," Vogt said.

But epilepsy is an obvious example of what can happen when that balance goes awry. And there is evidence that more subtle dysregulation could favor the development of schizophrenia. Vogt said the balance also appears to play a role in eating disorders.

And new research has shown that even brain tumors can sabotage the balance between excitation and inhibition to further their own growth. Glioblastoma multiforme, Vogt said, is a tumor that results from the uncontrolled growth of astrocytes: "it's not so far away to think about that."