TRAUMATIC BRAIN-DAMAGE PREVENTED BY THE NON-N-METHYL-D-ASPARTATE ANTAGONIST 3-DIHYDROXY-6-NITRO-7-SULFAMOYLBENZO[F]QUINOXALINE

The mechanisms of neuronal degeneration following traumatic head injur y are not well understood and no adequate treatment is currently avail able for the prevention of traumatic brain damage in humans. Traumatic head injury leads to primary (at impact) and secondary (distant) dama ge to the brain. Mechanical percussion of the rat cortex mimics primar y damage seen after traumatic head injury in humans; no animal model m imicking the secondary damage following traumatic head injury has yet been established. Rats subjected to percussion trauma of the cortex sh owed primary damage in the cortex and secondary damage in the hippocam pus. Morphometric analysis demonstrated that both cortical and hippoca mpal damage was mitigated by pretreatment with either the N-methyl-D-a spartate (NMDA) antagonist +/-)-2-carboxypiperazin-4-yl)-propyl-1-phos phonate (CPP) or the non-NMDA antagonist -dihydroxy-6-nitro-7-sulfamoy l-benzo[f]quinoxaline (NBQX). Neither treatment prevented primary dama ge in the cortex when therapy was started after trauma. Surprisingly, delayed treatment of rats with NBQX, but not with CPP, beginning betwe en 1 and 7 hr after trauma prevented hippocampal damage. No protection was seen when therapy with NBQX was started 10 hr after trauma. These data indicate that both NMDA- and non-NMDA-dependent mechanisms contr ibute to the development of primary damage in the cortex, whereas non- NMDA mechanisms are involved in the evolution of secondary damage in t he hippocampus in rats subjected to traumatic head injury. The wide th erapeutic time-window documented for NBQX suggests that antagonism at non-NMDA receptors may offer a novel therapeutic approach for preventi ng deterioration of the brain after head injury.