The overall objective of this research project is to determine whether or not prolonged or repetitive seizures (status epilepticus) occurring in the newborn period lead to permanent brain damage or contribute to the neuronal injury caused by a prior or concurrent insult to the immature brain. In addition, it will be ascertained whether or not seizures occurring prior to a hypoxic-ischemic insult reduces the severity of the ultimate brain damage. Sp3ecific Aims include: 1) to ascertain whether or not status epilepticus causes overt brain damage in developing rabbits; 2) to ascertain whether or not sub-threshold and damaging status epilepticus induced during early recovery following cerebral hypoxia-ischemia accentuates the ultimate brain damage to developing rabbits; 3) to ascertain whether or n not a sub-threshold episode of status epilepticus confers protection against a subsequent episode of status epilepticus and seizure-induced brain damage in developing rabbits; and 4) to ascertain whether or not a sub-threshold episode of status epilepticus occurring prior to cerebral hypoxia-ischemia confers protection against the ultimate brain damage in developing rabbits and, if so, by what mechanism. Developing rabbits will be used in all experiments and will be subjected to chemically induced status epilepticus using either kainic acid or flurothyl. Selected animals will undergo electrocorticographic monitoring and measurements of systemic physiologic variables; including blood pressure, heart rate, oxygen and acid-base status, blood glucose, lactate and ketone body concentrations. Rabbits undergoing status epilepticus with or without prior or subsequent cerebral hypoxia-ischemia will undergo neuropathologic processing and analysis to ascertain the distribution of severity of brain damage. Experiments are proposed in both unrestrained developing rabbits and in rabbits in which systemic physiologic variables are controlled to ascertain the contribution of alterations in body temperature, blood pressure, and oxygen and acid- based status to the ultimate brain damage caused either by status epilepticus, cerebral hypoxia-ischemia, or a combination of the two insults.
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