Glutamate Excitotoxicity: A Key Secondary Injury Mechanism of Traumatic Brain Injury and Spinal Cord Injury
Jiamei Hou, Kelena Klippel, Prodip Bose
Abstract
Glutamate excitotoxicity is one of the key factors in the pathophysiology of the secondary injury cascade following traumatic brain injury (TBI) and spinal cord injury (SCI). These neurotraumatic conditions remain major causes of long-term disability and mortality worldwide, yet therapeutic options remain limited. Excessive glutamate release after neurotrauma leads to the overactivation of glutamate receptors, triggering calcium influx and the activation of destructive enzymes and signaling pathways that drive progressive neuronal death and tissue degeneration. This review examines the molecular mechanisms of glutamate-mediated excitotoxicity in neurotrauma, particularly focusing on TBI and SCI, and evaluates current and emerging therapeutic strategies aimed at modulating glutamate levels, receptor activity, and downstream signaling pathways. Particular attention is given to glutamate receptor antagonists, agents enhancing glutamate clearance, and neuroprotective compounds. A critical analysis of preclinical successes versus clinical failures reveals key translational barriers, including narrow therapeutic windows, patient heterogeneity, poor drug penetration across the blood-brain barrier, and adverse off-target effects. Delayed treatment relative to the peak of excitotoxic activity has also limited clinical efficacy. This review highlights the importance of understanding the temporal dynamics of glutamate toxicity and the necessity for precisely timed, stratified therapeutic interventions. This work contributes to the broader scientific effort to develop more effective neuroprotective therapies by identifying the mechanistic underpinnings and translational challenges of anti-excitotoxic strategies. Given the global burden of TBI and SCI, advancing targeted interventions for glutamate excitotoxicity holds significant promise for improving neurological outcomes and quality of life for affected individuals.