Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury

• Published in: Science advances Vol. 9; no. 50; p. eadj2417
• Main Authors: MacLean, Mark A., Muradov, Jamil H., Greene, Ryan, Van Hameren, Gerben, Clarke, David B., Dreier, Jens P., Okonkwo, David O., Friedman, Alon
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 15.12.2023
• Subjects: Animals; Brain - metabolism; Brain Injuries, Traumatic - drug therapy; Electrocorticography; Memantine - pharmacology; Neuroscience; Rats; Receptors, N-Methyl-D-Aspartate - metabolism; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adj2417

Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals ( N = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial. Memantine inhibited cortical spreading depolarization and prevented neurobehavioral decline following traumatic brain injury.