Developing therapies to treat and prevent the acute and long-term consequences of concussion
“It’s one thing to study concussion and to want to know what’s going on, but what makes our team unique is our bent to understand the disease and make it better at the same time.”
This from Arthur Brown, PhD, a Western professor and Robarts Research Institute scientist at the Schulich School of Medicine & Dentistry.
“To the public, it probably sounds intuitive–why wouldn’t you want to try to find a way to treat it? But for scientists, it’s sometimes very daunting to think that way,” Brown laughed, “because the path is long and difficult.”
Brown said the effort of simultaneously advancing the understanding of concussion and developing therapeutic strategies is like “moving all your checkers up the board at the same time.”
It’s a complex game, filled with unknowns. But the promise of a big win for those who suffer from short- and long-term impacts of concussion is what drives him and fellow Robarts scientists, Greg Dekaban, PhD, and Schulich dean Mike Strong, MD, to develop therapies that could radically change its treatment and ease its devastating effects.
Collaborating within the context of the larger concussion research group at Western, the trio is developing therapeutics intended to:
Reduce the body’s inflammatory response to an assault on the brain, stopping the damage when the concussion occurs;
Harness neuroplasticity – the nervous system’s natural ability to rewire circuits—to enhance nerve sprouting that might underpin recovery; and
Prevent the development of chronic traumatic encephalopathy (CTE), a concussion-related dementia.
The team’s desire “to not only understand, but actually fix what happens in concussion” inspired former NHL star and Hockey Hall of Fame inductee Eric Lindros to galvanize the NHL Players Association to issue a fundraising challenge in support of their work.
That endorsement has helped validate the importance of their quest in their three core areas.
(L to R) Arthur Brown, Mike Strong, and Greg Dekaban in the lab at Robarts Research Institute at Western University.
Reducing inflammation – the body’s response to assault on the brain
The damage caused by a concussion is the result of two assaults to the brain—the initial injury, caused by the brain moving inside the skull or shock moving across the tissue, and the body’s natural immune response to the initial impact.
Building on ground-breaking work by Dekaban and Professor Emeritus Lynne Weaver, DVM, PhD, “our data suggests that in both the injured spinal cord and injured brain, the inflammatory response is perhaps a little more robust than it could be,” Brown said, “which may be because it’s been evolved to look after a wound that’s open to the environment and needs to be sealed up to fight infection.”
Unable to discriminate that difference, and as part of the very early inflammatory response to injury, our bodies send white blood cells into action, to sterilize bacteria by sticking to the blood vessel walls near the injury, squeezing into the tissue, which causes swelling.
Over a period of time, the nerves repair, but too much scarring can result in persistent headaches, dizziness, irritability, and difficulty with memory and attention.
In an effort to dial-back the body’s inflammatory response, Dekaban and Brown have created an antibody, which when delivered by IV within four hours of the injury, coats the white blood cells so that they can’t bind to the blood vessel wall and cause damage.
“We find that this acute intervention can reduce the infiltration of white blood cells into the injury area by about 50 per cent and reduce the inflammation. And we’re able to show in models of traumatic brain and spinal cord injury that the reduced inflammation improves outcomes,” Brown said.
The nervous system’s ability to rewire itself—through the process of neuroplasticity—is well-documented in instances of hemorrhagic stroke and spinal injury, in which undamaged areas of the brain can take over for the damaged ones.
The Brown and Dekaban labs are working to encourage similar growth in the nervous system in their novel approach to concussion.
“When the nervous system develops, there is a lot of growth signal present,” Brown said, “and the nerves talk to each other as they grow out. Once wired, the body responds by cementing these connections with a glue-like substance to prevent new ones from forming.
“Now imagine that you have an injury, and you’ve lost those inputs and connections. With that glue-like substance still present, your nervous system is limited in its ability to rewire. Our teams have identified at least one way for reducing that ‘glue’ in order to facilitate nerve sprouting. We’ve demonstrated this genetically through a mouse model, and now we are developing drugs to mimic what we can do genetically, in hopes of applying it to brain injury.”
Prevention of concussion-related dementia
Considered to be the end result of repeated, mild concussion injuries, chronic traumatic encephalopathy (CTE) presents as a cognitive disorder similar to frontal temporal dementia.
The key pathological feature of CTE is the abnormal deposition of a protein called ‘tau’, which is also involved in the pathology of Alzheimer’s disease.
“It’s believed that the aggregation of tau in the nerve processes makes them sick and impairs their ability to function. That’s basically what’s happening with dementia,” Brown explained.
“Mike (Strong) is pursuing the idea that the aggregation of tau is due to a chemical modification called phosphorylation and is interested in seeing if we modify that phosphorylation – by knowing the enzymes, and the specific proteins involved – if we could reduce their activity, and then maybe reduce the aggregation of tau and avoid dementia. That’s sort of the dream.”
Crucial to future clinical applications of the group’s findings will be identifying which concussed patients are part of the 85 per cent who recover fully on their own after the prescribed rest period, and those who are among the 15 per cent who struggle and would benefit most from therapeutic interventions.
“Meanwhile, we have to move up our therapies, so that we are ready to take advantage of the information when it comes, ”said Brown.
“We need to know who to treat. We’re not there yet, but I’m sure we’re going to get there, because we would like to do better. (We must) be able to treat concussion and post-concussion syndrome and avoid CTE. In order to do all these things, we still need to more fully understand the basic science of concussion.”