Cellular and Molecular Mechanisms of Secondary Neuronal Injury following Traumatic Brain Injury

Abstract

Excitotoxicity—the cascade of intracellular events initiated by excessive stimulation by neurotransmitters leading to intracellular calcium overload—is hypothesized to play an important role in mediating secondary neuronal injury after traumatic brain injury (TBI). While a variety of neurotransmitters could potentially trigger excitotoxic cell injury, glutamate is thought to be the primary contributor because of its potent effect on increasing intracellular calcium through ionotropic receptors (primarily NMDAR, but also kainate and calcium-permeable AMPAR). Microdialysis studies in rodents after both fluid percussion injury and controlled cortical impact have demonstrated a substantial increase in extracellular glutamate proportional to the severity of injury., A number of clinical observations also support the hypothesis that TBI increases extracellular glutamate. Multiple reports analyzing glutamate levels in cerebrospinal fluid (CSF) with the elevation often persisting beyond 1 week after injury., A prospective microdialysis study in patients suffering severe TBI showed an increase in extracellular glutamate in over 75% of patients; interestingly, values normalized over the course of 120 hours in 60% of these patients, but persistent elevations of extracellular glutamate were associated with increased mortality.