Making traumatic brain injury less harmful

Disease and treatment 27. feb 2024 3 min Professor Maiken Nedergaard Written by Kristian Sjøgren

New research shows what happens in traumatic brain injury, in which the brain swells and creates excessive and harmful pressure inside the skull. A researcher say that the discovery could lead to a new treatment approach to make traumatic brain injury much less harmful.

Cerebral oedema resulting from serious traumatic brain injury is a leading cause of death among young men.

Doctors have known about cerebral oedema and traumatic brain injury for millennia, but the understanding and treatment of cerebral oedema has remained the same for the past 60 years.

Doctors can treat people with cerebral oedema by opening up the skull to relieve the pressure or can administer mannitol – but neither is optimal.

Now a new study shows what actually happens in the brain following traumatic brain injury that leads to cerebral oedema. The research also shows how fairly simple medication can prevent the brain from swelling enough that it Is harmed.

“We lack good methods to treat people with cerebral oedema, primarily because we have poorly understood why this occurs – until now. Our study sheds whole new light on cerebral oedema and how to reduce the pressure in the brain,” explains co-author Maiken Nedergaard, Professor of Neurology and Physician, University of Copenhagen, Denmark and University of Rochester, USA.

The research has been published in Nature.

Traumatic brain injury activates many systems

Cerebral oedema has traditionally been understood as occurring locally in the brain at the site of the trauma. Then fluid flows from the blood vessels into the brain, which builds up harmful pressure.

However, the brain swells not only at the trauma site but also elsewhere.

This suggests a global phenomenon that probably involves the glymphatic system, a fluid system that removes metabolic waste products from the brain when we sleep. According to Maiken Nedergaard, the glymphatic system is probably involved when the brain swells in places other than the trauma site.

Further, noradrenaline, which keep us awake, influences the glymphatic system.

When noradrenaline is low, we fall asleep, and then the glymphatic system starts removing waste from the brain.

“In this study, we wanted to better understand the association between traumatic brain injury, cerebral oedema, noradrenaline and the glymphatic system. Noradrenaline increases in the body and brain following traumatic brain injury, and this may disable the glymphatic system so that it cannot remove the waste created in connection with cerebral oedema,” says Maiken Nedergaard.

She elaborates that the brain has great difficulty in managing dead brain cells, which leads to neuroinflammation and an increased risk of Alzheimer’s disease.

“The glymphatic system removes dead brain cells, so even though you might think that glymphatic fluid flowing into the brain in connection with cerebral oedema would be harmful, the fluid can certainly flow out again – as long as the system is active,” notes Maiken Nedergaard.

Traumatic brain injury in mice

The researchers carried out experiments with mice, inducing traumatic brain injury under brief anaesthesia. This ensured that the mice did not sleep, which would have disabled noradrenaline.

Then the researchers examined them for the development of cerebral oedema.

Some of the mice also received a noradrenaline antagonist that eliminated the effect of noradrenaline.

Antagonists protect the brain

The results showed very clearly that mice undergoing traumatic brain injury but receiving the noradrenaline antagonist did not develop cerebral oedema to the same extent and recovered more rapidly.

In contrast, the mice that did not receive the noradrenaline antagonist developed cerebral oedema not only at the trauma site but also on the opposite side of the brain. The trauma led to large spikes in the noradrenaline levels.

“These results indicate that using a noradrenaline antagonist may reduce the harmful effect of traumatic brain injury by ensuring that the brain does not swell. However, the study did not tell us why the noradrenaline antagonist appears to protect against cerebral oedema,” explains Maiken Nedergaard.

Keeping the cerebrospinal fluid flowing

The next experiments revealed that noradrenaline antagonists influence the inflow and outflow of fluid in the brain through the glymphatic system.

The researchers labeled the mice’s brain cells fluorescent green and opened up the lymph vessels in their necks.

They then observed how traumatic brain injury stopped the fluid from flowing through the lymphatic vessels, but administering a noradrenaline antagonist maintained the fluid flow, visualised as flowing green brain cell debris.

Maiken Nedergaard explains that administering a noradrenaline antagonist enables a group of muscle cells that normally contract but are hindered by noradrenaline to function normally again by inhibiting noradrenaline.

“We are convinced that this is why mice receiving a noradrenaline antagonist recover better following traumatic brain injury and do not develop cerebral oedema to the same extent,” adds Maiken Nedergaard.

Great clinical potential

Maiken Nedergaard says that brain surgeons have shown great interest in the study.

One reason is that the study indicates that one specific approach to people with traumatic brain injury can be harmful.

Serious traumatic brain injury sometimes makes the blood pressure drop, and doctors might consider administering noradrenaline to increase blood pressure and thus the blood flow to the brain.

However, the study indicates that this will probably be harmful because it slows down the glymphatic system’s ability to remove waste cells from the brain.

It is also well known that people receiving noradrenaline often do not recover very well, but this has been thought to result from the extent of the brain injury.

“The next step will be to show that we can also help people to reduce the negative effects of traumatic brain injury by administering a noradrenaline antagonist. We hope that this may also reduce the development of cerebral oedema and help to ensure that these people recover more rapidly,” concludes Maiken Nedergaard.

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