HYPOXIA MEDIATES N-METHYL-D-ASPARTATE SIGNALING RELATED SUSCEPTIBILITY TO TRAUMATIC BRAIN INJURY

Abstract

Cortical spreading depolarizations (CSDs) are an early hallmark of traumatic brain injury (TBI) and are associated with poor clinical outcomes, yet their underlying mechanisms remain poorly understood. We hypothesized that post-traumatic hypoxia promotes CSDs and impairs neurovascular responses. This study examined how hypoxia and CSDs affect neurobehavioral outcomes post-TBI and evaluated the effects of NMDAR antagonists as potential therapeutics. Using an animal model of single moderate TBI (N=67), we assessed its outcome variability (Chapter 2). TBI impaired neurological scores at 48 h post-impact (p<0.0001) and disrupted the neurovascular response to CSDs. Behavioral scores showed a bimodal distribution (R²=0.88; trough=7.01), categorizing animals into “susceptible” and “resilient” groups. Susceptible animals exhibited early cardiorespiratory dysfunction (lower HR and SpO₂ at hind paw and neck; p=0.02, p<0.001, p=0.01) and a significantly reduced neurovascular response to triggered CSDs, along with prolonged post-CSD oligemia. To explore the relationship between hypoxia and CSDs (Chapter 3), I used epidural electrodes and cranial window surgery. Animals that developed CSDs had lower mean SpO₂ (83.6%) compared to those that did not (92.2%). The co-occurrence of CSDs and hypoxia significantly altered the neurovascular response, with a 16% reduction in cerebral blood flow during the expected hyperemic phase, suggesting potential hypoperfusion and ischemia. In Chapter 4, I studied CSD-induced vascular responses in resilient vs. susceptible animals under hypoxia or following NMDAR antagonist treatment. Memantine reduced CSD incidence by 42–73% and mitigated cortical hypoperfusion. In a randomized pre- clinical trial, memantine treatment improved behavioral outcomes and preserved neurovascular function. This multi-modal investigation identified post-impact hypoxia as a key driver of CSDs and demonstrated that hypoxia and CSDs synergistically impair neurovascular regulation. Targeting these processes through oxygen support and NMDAR antagonism prevented secondary injury and improved outcomes. These findings may inform mechanism-based strategies for mitigating TBI susceptibility across injury severities.