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UA Study: Toxic, Liquefied Tissues Can Damage Brain For Months After Stroke

By Nicholas Gerbis
Published: Monday, February 26, 2018 - 5:05am
Updated: Tuesday, February 27, 2018 - 12:07pm

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For stroke survivors, brain injury doesn't always stop when the stroke has passed. Now, researchers at University of Arizona and Stanford University School of Medicine have moved one step closer to understanding why.

The study was published online in Neurobiology of Disease in January and will appear in the April 2018 print edition.

Like any other area of the body, the brain deals with damage via white blood cells that "eat" dead tissue, which is soon swept away and replaced with new cells. But in the brain, this process produces a thick liquid that can persist for months.

"In other tissues, following injury — for instance, the heart following a myocardial infarction — the inflammatory response, the blood cells, eat the dead tissue, and then they leave, they go about their way and the inflammatory response is resolved," said UA immunobiologist Kristian Doyle, who worked on the study.

But in the post-stroke brain, immune cells linger, awaiting the slow process of being pumped out through the small paravascular space around blood vessels. While there, they churn out degradative enzymes and other brain-harming molecules. Eventually, concentrations can rise to levels thousands of times the norm.

To protect the surrounding neurons, glial cells — the brain's scaffolding — contain the sludge within a basketlike scar. This scar consists of a layer of star-shaped glial cells called astrocytes, and measures about four to five cells thick.

But no one really knew how long the liquefaction lasted — or how toxic the liquid might be. What if some of it leaked out?

(Photo courtesy of Kristian Doyle, PhD / UA College of Medicine - Tucson)
A time-lapse showing dye injected into a damaged area of the mouse brain seven weeks post-stroke. The dye has spread past the glial scar barrier after six and 12 hours of injection.

"It's kind of an unexplored area of stroke research: exactly why the brain liquefies following stroke, what liquefaction in the brain consists of and how long it lasts, how toxic it is, and how well it's segregated from the rest of the brain," said Doyle.

To understand how much of a threat the liquefied brain might pose to living cells, Doyle and his coauthors tested its effects on mouse brain cells seven weeks following stroke. They then used dye to test how well the brain's protective scar segregated the plaque from the surrounding brain.

"And we found that, if we injected dye into the area of liquefaction, it gets across the scar that forms to seal it from the rest of the brain and into the surrounding brain tissue," said Doyle.

That leakage correlates with the atrophy that can occur for weeks and months following a stroke.

As to why the white blood cells produce so much destructive enzyme, Doyle has identified a surprising suspect: cholesterol.

The brain incorporates a lot of fats into its structure, mainly in the form of myelin, a whitish insulating sheath that boosts the speed of nerve impulses. Myelin is made mainly of proteins and fats.

When immune cells eat dead brain tissue, they bite off more fat than they can chew: The hydrophobic fats simply won't stay dissolved and, as they come out of solution, they form crystals that stab the cells' organelles. This jabbing prompts the immune cells to chronically churn out toxic degradative enzymes, some of which escape the scar.

The leakage could offer one explanation for why one-third of stroke survivors eventually experience dementia.

"It depends where the initial stroke occurred. If it occurred next door to an area important for memory, then the slow, low-grade leak of the molecules present in the area of liquefaction could be causing further injury in the area important to the memory, which is why it could be a driver of dementia," said Doyle.

The leaks produce less of a flood and more of a mild trickle; so, while they might inspire concern, they should not cause panic, says Doyle, who views the findings as an opportunity to improve stroke outcomes.

"What I'm interested in is, can we make the recovery faster and more effective if we can just expedite the removal of the area of liquefaction following stroke?"

Doyle and his colleagues are currently looking into treatments to make the brain build a stronger, more leak-proof scar faster. They are also working on using drugs to mediate cholesterol, which would mitigate the extent to which fats overwhelm immune cells in the brain.