Creatine increases survival and suppresses seizures in the hypoxic immature rat

The incidence of clinical seizures is highest in the newborn period. At this developmental stage seizures have many causes, with hypoxia and ischemia thought to be the most common. In rat pups hypoxia produces seizures most frequently at 10-12 d of age. Brain cellular energy metabolism increases between 5 and 25 d of age in the rat, as indicated in vivo by the phosphocreatine (PCr)/nucleoside triphosphate (NTP) ratio measured by P-31 nuclear magnetic resonance (NMR) spectroscopy. Brain PCr/NTP ratios are approximately the same in 10-12-d-old rats and human term newborns, the ages of high seizure susceptibility. Thus, low Cr or PCr may be important in susceptibility to hypoxic seizures in the metabolically immature brain. To test this hypothesis, rat pups were injected with Cr for 3 d before exposing them to hypoxia on postnatal d 10 or 20. Before and during hypoxia, the electrocortical activity or P-31 nuclear magnetic resonance spectra were measured. At 10 but not 20 d, Cr injections increased brain PCr/NTP ratios, decreased hypoxia-induced seizures and deaths, and enhanced brain PCr and ATP recoveries after hypoxia. Thus, Cr protects the metabolically immature brain from hypoxia-induced seizures and, perhaps, from cellular injury. These results may be directly relevant to the human newborn.