128 NMDA-Receptor Antagonism for the Prevention of Neurological Dysfunction in Traumatic Brain Injury: Results of a Randomized Pre-Clinical Trial. (April 2023)

• Record Type: Journal Article
• Authors: Maclean, Mark; Muradov, Jamil; Greene, Ryan; Friedman, Alon
• Is Part Of: Neurosurgery. Volume 69(2023)Supplement 1
• Page Start: 32
• Page End: 32
• Publication Date: 2023-04
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1227/neu.0000000000002375_128
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract : INTRODUCTION: Cortical spreading depolarization (CSD) represents a pathomechanistic target for neuroprotective therapy given the association with lesion development and poor outcomes following traumatic brain injury (TBI). METHODS: Experiments were conducted using 9-week-old Sprague Dawley rats. Daily neurobehavioral scores were recorded by trained, blinded observers. Using an established weight-drop model, animals received either single moderate (modTBI; n = 23) or four daily mild (rmTBI; n = 30) head impacts. Sham animals received brief anesthetic without TBI (n = 40). Animals underwent cranial window surgery and CSDs were electrically triggered by cortical stimulation; electrophysiological, imaging and blood-flow were monitored using intravital microscopy. Ketamine (100uM topical and 25 mg/kg IP, respectively) and memantine (10 mg/kg IP) were tested in vivo. Subsequently, a RCT was conducted (N=31) using memantine (10 mg/kg) or saline (2.5 cc/kg). Primary outcome: proportion of animals resilient to rmTBI (neurobehavioral scores ≥ 6 out of 12). RESULTS: In modTBI, and rmTBI animal models, intraperitoneal ketamine and memantine reduced the proportion of electrically triggered CSDs by 79-88%, and 42-73%, respectively. The average relative amplitude of change in ECoG were reduced by 70-75%, and 51-60%, respectively. Memantine significantly reduced spreading depression and cortical hypoperfusion following CSD. RCT animals in the memantine group were more likely resilient to injury (93% vs. 56%; p = 0.023) and had higher mean neurological scores (9.27 (SD 3.08) vs. 5.56 (SD 3.05)), p < 0.001) compared to saline. CONCLUSIONS: The NMDA-receptor antagonist memantine supresses CSDs and reduces pathological cerebral hypoperfusion in vivo following CSDs. In a rmTBI RCT, memantine prevented neurological decline.