PREVENTION OF TRAUMA-INDUCED NEURODEGENERATION IN INFANT RAT-BRAIN

Recent evidence implicates the endogenous excitatory neurotransmitters , glutamate (Glu) and aspartate, in the pathophysiology of traumatic i njury in the adult CNS, bur it is not known whether similar excitotoxi c mechanisms mediate traumatic injury in the immature CNS. Therefore, we developed a model of brain contusion injury in infant rats and used this model to study the nature and evolution of the acute cytopatholo gic changes and to evaluate the ability of Glu receptor antagonists to protect the immature brain against such changes. Seven-day-old rat pu ps were subjected to contusion injury and were killed 0, 0.5, 1, 2, 4, and 6 h later for histologic evaluation of the brain. Physical rearin g of thr dura and minor disruption of underlying brain tissue was note d at 0 h. At 30 min a discrete zone of neuronal necrosis began to appe ar at thr bolder of the trauma site; this zone progressively expanded over a period of 1 h. The cytopathologic changes closely resembled the type of changes Glu is known to cause; these changes consisted of swo llen dendrites, degenerating neurons with pyknotic nuclei and markedly swollen cytoplasm, and dark cells with vacuolated cytoplasm. The nonc ompetitive N-metyl-D-aspartate (NMDA) antagonist, dizocilpine maleate, when administered 30 min before or 1 h after trauma, significantly at tenuated the lesion. The competitive NMDA antagonist, ((2)-carboxypipe razine-1-yl)-propyl-1-phosphonate, was also neuroprotective. The o-3-h ydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist ,3-d ihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline did not significantly s uppress the lesion when given as three treatments (30 mg/kg each) 30 m in before plus 15 and 75 min after the insult. These findings suggest that traumatic injury in the infant rat brain is mediated by endogenou s excitotoxins (Glu and aspartate) acting at NMDA receptors and can be substantially mitigated by timely treatment with NMDA receptor antago nists.