Investigators working at Gladstone Institutes reported new insights into sleep disturbances and seizures that can be a late consequence of even mild traumatic brain injuries (TBI), and how we may one day best treat these conditions by targeting the complement pathway.
One of the consequences of TBIs is that patients commonly develop sleep disruption and epileptic seizures over time with a delayed onset first starting months or even years after the initial injury.
These appear to be caused by persistent, anatomically localized inflammation. However, there are currently no effective treatments to prevent this. Previously tested treatments that have targeted inflammation were not successful.
Principal investigator, Jeanne Paz, an associate investigator at Gladstone Institutes, emphasized that one important lesson from this research is that inflammation has both good and bad aspects.
"Sometimes we oversimplify, and I don't want people to conclude that inflammation in general is bad, because if you block C1q at the time of the injury, then the injury becomes much worse," Paz told BioWorld Science.
"Similarly, treating inflammation with anti-inflammatory drugs at the time of injury can be bad. For example, using steroids at the wrong time, right after injury, can cause death. Thus, it is critically important to understand that inflammation has a good side and a bad side if it persists too long, and the challenging part is to find how to best treat the bad without affecting the good side of inflammation."
Investigators discovered that the initiating complement factor, C1q, was highly expressed in the reticular thalamus of the brain of mice after TBI and this high expression was maintained for months after the initial injury, during a phase in which epileptic seizures with disruption of sleep spindles occurred.
Sleep spindles are an electroencephalogram (EEG) signature of healthy sleep, and an important component of memory consolidation. Interestingly, TBI can cause loss of sleep spindles with development of comorbid epileptic activities. Sleep spindles are also absent in schizophrenia patients.
A major break in the early stages of research first occurred in 2014 when Paz presented her observations at a symposium that chronic inflammation specifically occurred in the reticular thalamus of mice and rats after they had a cortical stroke or a trauma. Audience member Ben Barres alerted Paz to the existence of an antibody against C1q, which proved invaluably useful in her further research.
At the time, Paz and her colleagues were usure whether blocking C1q would provide benefit or exacerbation of the TBI model, given earlier results with anti-inflammatory approaches. "When we treated mice with this anti-C1q antibody after producing TBI on one side of the brain, we were really surprised to see that this antibody was able to prevent both the development of epileptic spikes and the loss of sleep spindles," she said.
Most significantly for translational potential, the investigators demonstrated that inhibition of C1q with an antibody at a later point, but not immediately after the injury, could prevent the onset of seizures and loss of sleep spindles.
Co-author Eleonora Aronica, a professor of neuropathology at the University of Amsterdam, examined post-mortem brains after brain trauma and also found upregulation of C1q long after the TBI event on the side of the brain that sustained TBI, but not the contralateral hemisphere.
The results support the idea that C1q antibodies may be useful for treating patients that had either a TBI or stroke.
"We think that if we can identify the chronic maladaptive components of inflammation and target it, then perhaps we can prevent adverse outcomes like post-TBI epilepsy. We have been looking for biomarkers of maladaptive inflammation and discovered that there is a huge upregulation of C1q in a brain region called the reticular thalamus in mice and this regulation could be good or bad, or both," Paz said.
In the work now published in Science, the team focused on mild TBI, because there, the injury itself does not directly damage the thalamus. They plan to examine patients that suffer from severe TBIs with severe epileptic seizures. From a translational perspective it is encouraging that there is already a C1q antibody in clinical trials for subjects with Guillain-Barre syndrome and the safety profile to date is promising.