Modeling pediatric head trauma: Mechanisms of degeneration and potential strategies for neuroprotection

We have developed a model for head trauma in infant rats in an attempt to s tudy mechanisms of neurodegeneration in the developing brain and were able to morphologically characterize two distinct types of brain damage. The fir st type or primary damage evolved within 4 hrs after trauma and occured by an excitotoxic mechanism. The second type or secondary damage evolved withi n 6-24 hrs and occured by an apoptotic mechanism. Primary damage remained l ocalized to the parietal cortex at the site of impact. Secondary damage aff ected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus, hippocampal dentate gyrus and striatum. Histologi cal evidence of delayed cell death was preceded by decrease of bcl-2- in co njunction with increase of c-jun-mRNA-levels, already evident at 1 hr after trauma. Increase of CPP32-like activity and elevated concentrations of oli gonucleosomes in affected brain regions represented additional findings to indicate that this secondary disseminated degenerative reaction is apoptoti c in nature. At the age of 7 days, secondary apoptotic damage was more severe than prima ry excitotoxic damage, but its severity declined with increasing age; In 7- day-old rats, NMDA antagonists protected against primary excitotoxic damage but increased severity of secondary apoptotic damage whereas the free radi cal scavenger SPBN, the tumor necrosis factor (TNF) inhibitor pentoxifyllin e and the antioxidant N-acetylcystein mitigated apoptotic damage. These findings demonstrate that in the developing rat brain apoptosis and n ot excitotoxicity determines neuropathologic outcome following head trauma. Whereas radical scavengers and TNF-inhibitors may prove useful in treatmen t of pediatric head trauma, great caution should be applied in regards to t he use of NMDA antagonists because of the inherent risk of apoptosis promot ion.