Traumatic brain injury is a leading cause of mortality and morbidity among young people. For the last couple of decades, it was believed that excess stimulation of brain receptors for the excitatory neurotransmitter glutamate was a major cause of delayed neuronal death after head injury, and several major clinical trials in severely head injured patients used blockers of the glutamate N-methyl-D-aspartate (NMDA) receptor. All of these trials failed to show efficacy. Using a mouse model of traumatic brain injury and quantitative autoradiography of the activity-dependent NMDA receptor antagonist MK801, we show that hyperactivation of glutamate NMDA receptors after injury is short-lived (<1 h) and is followed by a profound and long-lasting (>7 days) loss of function. Furthermore, stimulation of NMDA receptors by NMDA 24 and 48 h postinjury produced a significant attenuation of neurological deficits (blocked by coadministration of MK801) and restored cognitive performance 14 days postinjury. These results provide the underlying mechanism for the well known but heretofore unexplained short therapeutic window of glutamate antagonists after brain injury and support a pharmacological intervention with a relatively long (>24 h) time window easily attainable for treatment of human accidental head injury.H ead trauma is a leading cause of mortality and morbidity among young people in the western world (1). Traumatic and ischemic brain injury triggers a large, transient increase in excitatory amino acid transmitter efflux in the brain of experimental animals and human subjects (2-6). Glutamate activation of the N-methyl-D-aspartate (NMDA) receptor (NMDAR), which is a ligand-gated ion (calcium and sodium) channel, results in channel opening and ion influx into the cell. It has been suggested that this process mediates delayed excitotoxic neuronal death after brain ischemia and trauma (7,8), although the concept is not universally accepted (9, 10). Support for the involvement of NMDAR activation in neuronal death after brain injury has come from numerous studies showing that NMDAR antagonists reduce cell death and improve outcome in animal models of traumatic brain injury (TBI) and stroke. NMDAR antagonists appear to be most efficacious when given before or immediately after the insult and lose efficacy if administered Ͼ30-60 min postinjury (11)(12)(13)(14)(15).Microdialysis studies of extracellular glutamate in human TBI and stroke patients suggested that the increase in glutamate in humans is more sustained [6 h to several days (7, 8)] than in rodents, where it only lasts minutes (2-6). This result may have contributed to a decision to administer NMDAR antagonists in clinical trials of head injury for several days rather than once after severe nonpenetrating injury. All clinical trials of NMDAR antagonists to date failed to show efficacy. Furthermore, some of these trials had to be stopped prematurely because of increases in mortality and morbidity in the drug arm of the stroke trials (16-18), suggesting that prolonged bloc...

Dynamic changes in neuroinflammation and glutamate NMDA receptors (NMDAR) have been noted in traumatic and ischemic brain injury. Aim Here we investigate the time course and regional distribution of these changes and their relationship with atrophy in a rat model of penetrating brain injury. Materials & methods Quantitative autoradiography, with the neuroinflammation marker [3H]PK11195 and the NMDAR antagonist [125I]iodoMK801, was performed on brains of animals subjected to a unilateral wireknife injury at the level of striatum and killed 3 – 60 days later. Regional atrophy was measured by morphometry. Results The injury produced large increases in [3H]PK11195 binding density in cortical and septal regions adjacent to the knife track by day 7, with modest increases in the striatum. [125I]iodoMK801 binding was reduced in cor tical and hippocampal regions showing marked neuroinflammation, which showed marked atrophy at subsequent time points. Conclusion These results indicate that neuroinflammaton and loss of NMDAR precede and predict tissue atrophy in cortical and hippocampal regions.