Abstracts

RATIONALE: Cell death in both hypoxia/ischemia and seizures results from over activation of glutamate receptors which leads to excessive Ca2+ influx. Direct evidence is lacking, however, that shows the possible detrimental effect of seizures on the underlying brain damage. To determine whether status epilepticus increases neuronal injury caused by perinatal hypoxia-ischemia, seizures were induced by kainate(KA)in immature rats following combined unilateral carotid ligation and hypoxia. METHODS: P9 rat pups (n=11) underwent unilateral carotid ligation followed by global hypoxia (6% O2 for 1 h). After 1 hour of recovery, 6 pups were injected with KA (2mg/kg,i.p,), and 5 with PBS. KA induced seizures for over 3 hours. The animals were perfused at 48h, and brain were processed for in situ end labelling(ISEL) for DNA fragmentation. ISEL positive neurons from one ventral hippocampal section from each animal were counted and compared using Mann-Whitney Rank Sum Test. RESULTS: Nearly continuous seizures were noted in most pups during 1h of hypoxia. Hypoxia-ischemia caused regionally specific cell death involving both white and gray matter. The most consistently affected regions were as follows: cingulum of corpus callosum (bilaterally), cingulate cortex (layer II), deep layers of cortex immediately adjacent to periventricular white matter, hippocampus (CA3>CA1>DG), amygdala, striatum, thalamus and pyriform cortex. KA seizures increased cell death in the hippocampus, thalamus and pyriform cortex and, in some animals, extended the injury to involve frontal and parietal cortices. Hippocampal neuronal death not only extended over the temporal-septal axis, but involved the side contralateral to carotid ligation in 3/5 animals. The number of ISEL positive neurons was significantly increased in the hippocampus after KA status (p=0.017, 103 b23 vs. 283 b 67). CONCLUSIONS: While KA-induced seizure causes no cell death in the immature brain, it accentuates hypoxic-ischemic brain injury. This may be due to cumulative effect of both hypoxia-ischemia and seizures in causing high local concentration of glutamate. (Supported by K08NS-02068 and R01NS-31718).