Blocking immune system molecule in mice may help prevent disabilities after brain injury - study
Traumatic brain injury affects 69 million people worldwide per year and is a leading cause of disability in children and adults.
An image of the human brain (photo credit: REUTERS)
Blocking an immune system
molecule that accumulates after traumatic brain injury could
significantly reduce the injury’s detrimental effects, according to a
recent mouse study published in the peer-reviewed journal Science.
The
cerebral cortex, the part of the brain involved in thinking, memory and
language, is often the primary site of head injury because it sits
directly beneath the skull. However, researchers found that another
region near the center of the brain that regulates sleep and attention,
the thalamus, was even more damaged than the cortex months after the
injury.
This may
be due to increased levels of a molecule called C1q, which triggers a
part of the immune system called the classical complement pathway. This
pathway plays a key role in rapidly clearing pathogens and dead cells
from the body and helps control the inflammatory immune response.
C1q plays both helpful and harmful roles in the brain. On the one
hand, accumulation of C1q in the brain can trigger abnormal elimination
of synapses – the structures that allow neurons to communicate with one
another – and contribute to neurodegenerative disease. On the other
hand, C1q is also involved in normal brain development and protects the
central nervous system from infection.
In the case of traumatic brain injury,
the researchers found that C1q lingered in the thalamus at abnormally
high levels for months after the initial injury and was associated with
inflammation, dysfunctional brain circuits and neuronal death. This
suggests that higher levels of C1q in the thalamus could contribute to
several long-term effects of traumatic brain injury, such as sleep
disruption and epilepsy.
The brain (credit: INGIMAGE)
C1q
does provide some protection for the brain during traumatic injury,
however. When the researchers used genetically engineered mice that lack
C1q at the time of trauma, the brain injury appeared much worse. This
suggests that C1q is likely very important right when the injury happens
in preventing cell death.
The
researchers collaborated with scientists at the biopharmaceutical
company Annexon Biosciences to see if they could avoid C1q’s detrimental
effects without losing its protective ones. They found that treating
mice with an antibody that blocks C1q 24 hours after brain injury
prevented detrimental effects like chronic inflammation and neuronal
loss in the thalamus.
Additionally, antibody treatment helped restore
disrupted sleep spindles – these are normal brain rhythms during the
early stages of sleep that are important for memory consolidation. It
also prevented the development of epileptic spikes, or abnormal
fluctuations in brain activity, which can disrupt cognition and
behavior.
Traumatic
brain injury can happen to anyone. It affects 69 million people
worldwide per year and is a leading cause of disability in children and
adults. Yet there are currently no therapies available to prevent the
long-term disabilities that can result from brain trauma, such as
epilepsy, sleep disruption and sensory processing difficulty.
The researchers believe that targeting C1q after a brain injury
could have protective benefits and help prevent some of the devastating
consequences. Our study also answered some big questions in the field
about where and how changes happen in the brain after trauma, and which
ones actually cause deficits.
It
remains unknown whether blocking C1q could also prevent epileptic
seizures that develop after severe traumatic brain injury. Researchers
are looking for biomarkers that would help identify people at high risk
of developing epilepsy and working to understand the basic mechanisms
leading from traumatic brain injury to epilepsy. There is no cure yet
for post-traumatic epilepsy.
The
lab will continue working to expand our understanding of what happens
in the brain after injury. Next, the researchers want to focus on
whether they can target C1q to prevent the convulsive seizures often
reported among people with severe traumatic brain injuries.
C1q
inhibitors are currently being tested in clinical trials for an
autoimmune disorder known as Guillain-Barré syndrome. This could help
accelerate treatment development for patients with traumatic brain
injury.
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