Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain

Abstract

Age dependency of apoptotic neurodegeneration was studied in the developing rat brain after percussion head trauma. In 7-day-old rats, mechanical trauma, applied by means of a weight drop device, was shown to trigger widespread cell death in the hemisphere ipsilateral to the trauma site, which first appeared at 6 hours, peaked at 24 hours, and subsided by 5 days after trauma. Ultrastructurally, degenerating neurons displayed features consistent with apoptosis. A decrease of bcl-2 in conjunction with an increase of c-jun mRNA levels, which were evident at 1 hour after trauma and were accompanied by elevation of CPP 32-like proteolytic activity and oligonucleosomes in vulnerable brain regions, confirmed the apoptotic nature of this process. Severity of trauma-triggered apoptosis in the brains of 3- to 30-day-old rats was age dependent, was highest in 3- and 7-day-old animals, and demonstrated a subsequent rapid decline. Adjusting the mechanical force in accordance with age-specific brain weights revealed a similar vulnerability profile. Thus, apoptotic neurodegeneration contributes in an age-dependent fashion to neuropathological outcome after head trauma, with the immature brain being exceedingly vulnerable. These results help explain unfavorable outcomes of very young pediatric head trauma patients and imply that, in this group, an antiapoptotic regimen may constitute a successful neuroprotective approach.