Brain Star Award winner, Dr. Mark A. MacLean

Mark A. Maclean

Dr. Mark A. Maclean, Dalhousie University

Memantine Inhibits Cortical Spreading Depolarization and Improves Neurovascular Function Following Repetitive Traumatic Brain Injury. Mark A. MacLean, Jamil H. Muradov, Ryan Greene, Gerben Van Hameren, David B. Clarke, Jens P. Dreier, David O. Okonkwo, Alon Friedman. Science Advances, 2023, 9(50): eadj2417.

Memantine shows promise as therapy to improve outcome following traumatic brain injury

Despite decades of research, no medical therapies have yet received approval for targeting mechanisms underlying the short- and long-term consequences of traumatic brain injury (TBI). Cortical spreading depolarization (CSD) is a process that commonly occurs after TBI, altering electrical signals and blood flow in the brain. Patients that experience this phenomenon have worse clinical outcomes. In a promising pre-clinical study, Dr. Maclean and colleagues have identified a drug that inhibits cortical spreading depolarization and improves outcomes following repetitive traumatic brain injury.

In this study, the researchers used a rodent model to investigate the effects of CSD in the setting of concussion. The team tested various drugs to see which inhibited CSD. They identified Memantine, a known and safe treatment for Alzheimer’s disease, as an inhibitor of CSD. Memantine also reduced problematic changes in brain activity and improved the blood flow response to injury. Given these findings, they carried out a randomized, blinded pre-clinical trial of memantine for the treatment of repetitive concussion. The key finding of this work is that memantine prevented neurological decline with no observable side effects.

Recent human studies had demonstrated that ketamine, another drug in the same class as memantine, inhibited CSD following TBI. However, ketamine has many unwanted side effects that would preclude its use in the setting of mild TBI (e.g. in sporting athletes that experience repetitive concussive head impacts). As such, the researchers sought out to find an alternative therapy with a favorable side effect profile, and memantine emerged as a very promising candidate. This work sets the stage for future mechanism-directed clinical trials in humans with acquired brain injuries.

About Dr. Mark A. MacLean

Dr. MacLean is a neurosurgery resident physician in Halifax, Nova Scotia. He carried out this work in the laboratory of neuroscientist, Dr. Alon Friedman (Dalhousie University, Nova Scotia Health Authority). Upon completion of his residency in June, Dr. MacLean is pursuing a fellowship in neurotrauma under the supervision of Dr. David Okonkwo, University of Pittsburgh, USA. His goal is to develop a multi-disciplinary neurotrauma research program with an emphasis on translating laboratory science to the clinical setting, using a “bench-to-bedside” approach.

Sources of funding

Dr. MacLean received a Neurosurgery Research Education Foundation and Academy of Neurological Surgeons Research Fellowship Grant to support this work. Drs. MacLean and Friedman received a Canadian Institutes of Health Research Project Grant. Other funding sources include: European Research Area Network Neuron Award, Deutsche Forschungsgemeinschaft (DFG) (German Research Council), and BMBF Bundesministerium fuer Bildung und Forschung (Era-Net Neuron EBio2).