NREF Success Story:
Mark MacLean, MD, MSc
In 2021-22, Mark MacLean, MD, MSc, of Dalhousie University, was awarded the NREF & Academy of Neurological Surgeons Research Fellowship Grant for his project titled “Exploring Mechanisms Underlying Mild Traumatic Brain Injury-Related Microvasculopathy.”
Mentored by Alon Friedman, MD, PhD, Dr. MacLean’s NREF-funded research resulted in a manuscript published in the Science family of journals.
Dr. MacLean has provided the following overview of the study and its findings:
Decades of research have been directed toward discovering treatments to reduce the effect of trauma on the nervous system. Despite this, no medical therapies have received approval for targeting mechanisms underlying the short- and long-term consequences of traumatic brain injury. Cortical spreading depolarization (CSD) is a process that commonly occurs after traumatic brain injury.
It alters the electrical signals and blood flow of the brain. It can occur in the “healthy” brain without severe harm, as is observed with migraine aura. However, in the setting of traumatic brain injury, it can be harmful. Patients that experience this phenomenon have worse clinical outcomes. CSD represents a promising target for therapy in the setting of TBI.
In this study, we used a rodent model of closed head injury to examine CSD following moderate and mild (repetitive) concussive head impacts. We examined CSD in live rodents during microsurgery, which included direct monitoring of the rodent’s brain electrical activity and blood flow response. We then tested therapies to inhibit CSD. In recent prior studies, the NMDA-receptor antagonist Ketamine has been found to block CSD and improve outcomes in humans. The issue is that ketamine has many unwanted side effects, which would certainly preclude its use in sporting athletes with repetitive concussive head impacts. As such, we sought out to find an alternative with a favorable side effect profile. We were pleased to find the NMDA-receptor antagonist memantine inhibited CSD just as effectively as ketamine, with no observable side effects (memantine is known previously for its safety and efficacy as a treatment for Alzheimer’s disease). In our study, memantine also improved the brain’s electrical activity and blood flow response following traumatic brain injury. Finally, we tested memantine against “placebo” in a blinded, randomized trial in the animals. Memantine prevented neurological decline following repetitive concussive brain impacts.
In summary, our work demonstrates that the drug memantine effectively reduces the harms of CSD without inducing any side effects. It also improves neurological outcome in animals following repetitive concussive brain injury. This work sets the stage for future clinical trials in humans with acquired brain injuries.