Prevention of trauma-induced neurodegeneration in infant and adult rat brain: Glutamate antagonists

The mechanisms of neuronal degeneration following traumatic head injury are not well understood and no adequate treatment is currently available for the prevention of traumatic brain damage in humans. Seven day old rat pups were subjected to mechanical percussion of the head. Cortical damage in infant rats was reduced by pre-treatment with the N-methyl-D-aspartate (NMDA) antagonists dizocilpine (MK-801) or 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP). The AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) did not significantly suppress cortical damage in infant rats. In adult rats, traumatic head injury leads to primary (at impact-cortex) and secondary (distant- hippocampus) damage to the brain. Morphometric analysis demonstrated that both cortical and hippocampal damage was mitigated by pre-treatment with either the NMDA antagonist CPP or the non-NMDA antagonist NBQX. Neither treatment prevented primary damage in the cortex when therapy was started after trauma. Delayed treatment of rats with NBQX, but not with CPP, beginning between 1 and 7 h after trauma prevented the hippocampal damage. No protection was seen when therapy with NBQX was started 10 h after trauma. These data indicate that NMDA antagonists may possess better neuroprotective properties against excitotoxic processes triggered by traumatic brain injury in young individuals whereas AMPA antagonists may be more beneficial in adults.