The overall objective of the present research protocol is to determine whether or not prolonged or repetitive seizures occurring in the newborn period lead to permanent damage or contribute to the neuronal injury caused by a prior or concurrent insult to the immature brain.
Specific aims i nclude: 1) to ascertain the threshold dose of specific convulsant drugs required to produce one or more prolonged or brief, repetitive seizures in developing rats; 2) to determine whether or not either multiple prolonged seizures or brief, repetitive seizures cause brain damage in developing rats not previously subjected to cerebral hypoxia- ischemia 3) to determine whether or not the threshold dose of a specific convulsant agent known to produce seizures in normal developing rats is altered by prior brain damage caused by hypoxia-ischemia; 4) to determine whether or not the brain damage caused by multiple prolonged or brief, repetitive seizures following hypoxia-ischemia is greater than caused by hypoxia-ischemia alone in developing rats; 5) to determine the extent to which glucose supplementation during status epilepticus alters mortality and ultimate brain damage arising from status epilepticus occurring following cerebral hypoxia-ischemia; and 6) to investigate underlying mechanisms of tissue injury produced by status epilepticus superimposed on cerebral hypoxia-ischemic, including measurements of cerebral blood flow and metabolism. To accomplish these goals, we plan to use the following analytical techniques: 1) the iodo-[14C]-antipyrine method to measure regional cerebral blood flow; 2) the 2-deoxy-[14C]-glucose technique to measure regional cerebral glucose utilization; 3) in vivo analysis of glycolytic and Krebs cycle intermediates in high-energy phosphate reserves in brain tissue; and 4) light microscopic analysis of brain specimens. Seven-day postnatal rats will be subjected to prolonged or repetitive seizures with one of 4 convulsant drugs; including bicucculline, kainic acid, flurothyl or mercaptopropionic acid. Other immature rats will be subjected to unilateral common carotid artery occlusion combined with exposure to 8% oxygen for either 1.5 or 2 hours. Following hypoxia-ischemia, the animals will receive varying concentrations of a convulsant drug necessary to ascertain the threshold dose necessary to produce seizures and to determine any accentuating effect of prolonged or repetitive seizures on the incidence and severity of brain damage. Additional studies will investigate the regional cerebrovascular and metabolic responses of immature rats to prolonged or repetitive seizures with or without cerebral hypoxia-ischemia. Experiments also will be accomplished to ascertain the protective role of glucose supplementation during prolonged or repetitive seizures on mortality and ultimate brain damage.
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