New research from the University of Copenhagen shows that the brain’s glymphatic system malfunctions after a stroke and drowns the brain in its own fluid. The findings could provide new opportunities for saving lives after stroke.
The glymphatic system, which was discovered recently, normally clears waste from the brain while we sleep.
However, after a stroke, the cerebrospinal fluid that fills the glymphatic system may play a negative role and cause severe brain damage.
Researchers from the University of Copenhagen and other universities recently showed that, after a stroke, the cerebrospinal fluid flows into the brain and causes it to swell. Since the brain cannot expand more than the skull allows, the pressure on the brain can become so great that it results in major damage to brain tissue or even death.
The discovery provides a whole new insight into stroke, one of the world’s major causes of death.
“Our results show for the first time that the glymphatic system plays a key role in the swelling the brain experiences after a stroke. It can affect how we treat people when they get a blood clot in the brain,” explains one author, Maiken Nedergaard, Professor, Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen.
The study has been published in Science.
Oedema can occur several weeks after a stroke
Oedema, or fluid build-up, in the brain is the most important complication of acute brain damage.
When the brain is damaged after a stroke or accident, it swells up and the pressure causes secondary damage in the hours following the initial trauma.
Doctors divide oedema into two main types: primary and secondary. Primary oedema occurs immediately in the hours following the trauma; the secondary manifestation can occur much later.
Sometimes doctors find that a person enters the emergency room and can still move their legs. But after some time, the brain swells, and the pressure on various areas of the brain destroys the brain cells and leads to paralysis.
Researchers and doctors had been convinced that the extra fluid that flows into the brain during a stroke and causes the swelling comes from the blood. The new study suggests that cerebrospinal fluid from the glymphatic system is the cause.
“It's kind of strange that people never previously thought that the brain is surrounded by half a litre of fluid and that this is what flows into the brain when part of the brain dies,” says Maiken Nedergaard.
Blood clot sends the brain into a death spiral
The research, which was carried out on mice, shows what happens when oedema occurs.
In a stroke, a blood clot initially blocks a blood vessel in the brain.
When the brain cells no longer receive blood and nutrients, after a few minutes they begin to depolarize, nearly completely losing the transmembrane ion gradients that regulate all internal processes in the cells.
The release of energy from the individual cells spreads to the neighbouring cells, and like a domino effect, an electric wave is created that spreads outward from the epicentre.
The depolarization also causes the brain cells to release large quantities of potassium and neurotransmitters, causing the muscle cells in the blood vessels in the brain to contract and cut off blood supply further.
The cerebrospinal fluid then flows into the vacuum caused by the shrinking of the blood vessels, causing the brain to swell.
The swelling can further block the blood supply and thus send the brain into a death spiral.
“The brain cells drown in the cerebrospinal fluid as the brain begins to swell. Depolarization and death waves can continue for several days or even weeks after a stroke and aggravate the damage further,” explains Maiken Nedergaard.
Medicine can slow the development of oedema
Grethe Andersen, Professor and Consultant at the Department of Neurology of Aarhus University Hospital, says that the discovery indicates that doctors should try to prevent primary oedema much earlier than they do today.
Grethe Andersen is not involved in the study but has read it and thinks it is very interesting and thought-provoking.
She also believes that it opens up new opportunities to treat a stroke in the early stages.
“The study indicates that inhibiting several proteins that transport fluid into the cells can slow the development of oedema. However, the treatment must be administered extremely quickly to be effective,” says Grethe Andersen.
Maiken Nedergaard reaches the same conclusion in the study.
Ambulance crews should administer medicine if they suspect stroke
The specific molecules the medicine should target are called aquaporin-4.
Grethe Andersen and Maiken Nedergaard both imagine that finding medicine that inhibits aquaporin-4 could save many lives if it is administered early enough.
Grethe Andersen explains that the medicine must be injected intravenously by ambulance crews within 1 hour of a stroke. The medicine must be able to cross the blood–brain barrier so it can enter and affect the brain.
“This medicine needs to work right away, and Denmark has a very well-functioning ambulance system that ensures that ambulances reach anyone within 12 minutes. If well-trained ambulance crews suspect a stroke, they can administer the medicine to contain the swelling until the person arrives at a hospital, where doctors can begin to remove the blood clot,” says Grethe Andersen, who also observes that this medicine should be combined with everything that doctors already do for the people who have had a stroke.
Medicine for altitude sickness may slow the development of oedema
Grethe Andersen has an idea for treating people with stroke to avoid oedema.
According to her, initial candidates for investigation could be medicine taken for altitude sickness because this targets aquaporin-4.
“This medicine inhibits the fluid-transporting channels, so this treatment might provide more time before the person with a stroke arrives at the hospital and the blood clot can be treated. Obviously, this needs to be thoroughly investigated first in clinical trials and may not be possible at all, but this is the perspective,” says Grethe Andersen.
“Cerebrospinal fluid influx drives acute ischemic tissue swelling” has been published in Science. In 2018, the Novo Nordisk Foundation awarded a grant to Grethe Andersen for the project REDS – Rheo-erythrocrine Dysfunction in Stroke and Remote Ischemic Conditioning.
