Scientists have discovered a protein interaction that may protect areas of the brain from stroke’s second wave of damage and could serve as a potential drug target for improving outcomes in humans.
Researchers are still exploring all the complexities of stroke, which is the leading cause of disability worldwide and the second leading cause of death. While stroke initially damages the brain via loss of blood supply, it also unleashes a second wave of destruction upon the penumbra—the tissue that envelopes the core stroke site—as damaged brain cells release excessive amounts of the neurotransmitter glutamate.
Preserving the penumbra is a high priority because damage to the area greatly contributes to disability after stroke. However, current pharmacological approaches aiming to save the area haven’t been successful, likely due to unspecific targeting and the impact of glutamate, according to study findings published April 20 in Science Translational Medicine.
Lead researcher Lynn Bitar and colleagues found that blocking the enzyme autotaxin (ATX) in mice can protect regions of the brain that surround the immediate stroke area and therefore improve recovery.
The researchers, part of the Rhine Main Neuroscience Network and the University Medical Center of the Johannes Gutenberg University in Mainz, Germany, examined cerebrospinal fluid and serum samples from 21 stroke patients and 20 healthy donors. They found that patients had much higher levels of ATX—which synthesizes receptors for the lipid LPA, tied to high glutamate activity—up to two weeks after a stroke.
In a subsequent mouse study, the team discovered that delivering an ATX inhibitor—PF8380—at various intervals after stroke shrank damaged brain regions and quelled the cortex’s hyperexcitability that had been triggered by LPA. ATX inhibition in the animal model improved stroke outcome, suggesting the ATX-LPA signaling may have translational potential for future therapeutics.
The researchers did caution that their work is limited by a small sample size and should be confirmed in larger studies.
Prior studies in mice have explored other pathways also aiming to protect the brain from stroke. For example, neuroscientists at the University of Pittsburgh identified a novel drug, TAT-DP-2, that they believe could protect the brain from neuronal tissue damage. The drug disrupts a potassium ion channel that’s key to regulating neuronal death and led to reduced brain damage after stroke when administered in mice.
Another study examined the role of neutrophils, a naturally occurring protein, in blocking an inflammatory immune response and aiding stroke recovery in mice.