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Creatine increases survival and suppresses seizures in the hypoxic immature rat
D Holtzman1, A Togliatti, I Khait
1Department of Neurology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Insights
Creatine supplementation protects newborn rat brains from seizures caused by hypoxia. This finding suggests creatine may prevent hypoxic brain injury in human newborns.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Seizures are most common in newborns, often caused by hypoxia and ischemia.
- Rat pups aged 10-12 days exhibit high susceptibility to hypoxia-induced seizures.
- Brain energy metabolism, indicated by the phosphocreatine (PCr)/nucleoside triphosphate (NTP) ratio, increases with age in rats.
Purpose of the Study:
- To investigate the role of creatine (Cr) in protecting the metabolically immature brain from hypoxia-induced seizures.
- To test the hypothesis that low creatine or phosphocreatine levels contribute to seizure susceptibility in hypoxic conditions.
Main Methods:
- Rat pups were administered creatine for 3 days prior to hypoxic exposure at postnatal days 10 or 20.
- Electrocortical activity and 31P nuclear magnetic resonance (NMR) spectra were measured before and during hypoxia.
- Brain PCr/NTP ratios were assessed to evaluate cellular energy metabolism.
Main Results:
- Creatine administration increased brain PCr/NTP ratios at postnatal day 10, but not day 20.
- Creatine significantly decreased hypoxia-induced seizures and mortality in 10-day-old rat pups.
- Enhanced recovery of brain PCr and ATP levels was observed after hypoxia in creatine-treated pups.
Conclusions:
- Creatine supplementation protects the metabolically immature brain against hypoxia-induced seizures.
- Creatine may offer protection against cellular injury resulting from hypoxic events in newborns.
- These findings have potential implications for managing hypoxic brain injury in human newborns.
Abstract:
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 31P 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 31P 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.