Neurochemical characterization of traumatic brain injury in humans

Trauma is the leading cause of death in individuals between the ages of 1 a nd 44 years. And, in the case of severe head injury mortality can reach as high as 35-70%. Despite this fact, there has been little progress in the de velopment of effective pharmacological agents to protect brain injured pati ents. To date, there is little data on the mechanisms involved in neuronal cellular insult after severe head injury, especially in humans. Glutamate a cts both as a primary excitatory neurotransmitter and a potential neurotoxi n within the mammalian brain. Evidence indicates that hyperactivity of the glutamate system contributes to neuronal death in brain trauma. Also, in an imal models of neurotrauma, this neural injury is followed by gliosis which has been linked to the severity of brain injury. To investigate the glutam ate system in brain trauma, we carried out [H-3]glutamate and [H-3]MK801 (a noncompetitive NMDA-receptor antagonist) binding and [H-3]glutamate uptake assays in human cerebral cortex preparations obtained from severely brain injured and control victims. Additionally, to investigate gliosis following brain injury, we performed GFAP immunohistochemistry. There were no signif icant differences in [H-3]glutamate binding (affinity or density of sites) between the control and head injured groups. In contrast, cerebral cortical [H-3]MK801 binding revealed both a significant increase in the density of sites (B-max) and a decrease in the dissociation constant (Kd) in the head injured group when compared to controls. There were no significant differen ces in [H-3]glutamate uptake between groups. The injured brains presented a n increased number of GFAP-positive astrocytes and more intense GFAP reacti on in comparison to control brains. In the context of traumatic brain injur y, our results encourage further investigation into compounds capable of se lective modulation of NMDA receptor subtype in humans while also therapeuti cally manipulating glial cell responses following brain trauma.