N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain

Morbidity and mortality from head trauma is highest among children, No anim al model mimicking traumatic brain injury in children has yet been establis hed, and the mechanisms of neuronal degeneration after traumatic injury to the developing brain are not understood. In infant rats subjected to percus sion head trauma, two types of brain damage could be characterized, The fir st type or primary damage evolved within 4 hr and occurred by an excitotoxi c mechanism. The second type or secondary damage evolved within 6-24 hr and occurred by an apoptotic mechanism. Primary damage remained localized to t he parietal cortex at the site of impact. Secondary damage affected distant sites such as the cingutate/retrosplenial cortex, subiculum, frontal corte x, thalamus and striatum, Secondary apoptotic damage was more severe than p rimary excitotoxic damage. Morphometric analysis demonstrated that the N-me thyl-D-aspartate receptor antagonists 3-(2-carboxypiperazin-4-yl) propyl-1- phosphonate and dizocilpine protected against primary excitotoxic damage bu t increased severity of secondary apoptotic damage. 2-Sulfo-alpha-phenyl-N- tert-butyl-nitrone, a free radical scavenger, did not affect primary excito toxic damage but mitigated apoptotic damage. These observations demonstrate that apoptosis and not excitotoxicity determine neuropathologic outcome af ter traumatic injury to the developing brain. Whereas free radical scavenge rs may prove useful in therapy of head trauma in children, N-methyl-D-aspar tate antagonists should be avoided because of their propensity to increase severity of apoptotic damage.