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In vivo development of brain phosphocreatine in normal and creatine-treated rabbit pups
D Holtzman1, I Khait, R Mulkern
1Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Insights
Creatine supplementation in young rabbits prevents seizures caused by low oxygen by enhancing brain energy reserves. This study shows creatine boosts brain phosphocreatine levels, crucial for preventing hypoxic seizures in developing animals.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Developing brains have unique metabolic vulnerabilities.
- Hypoxia-induced seizures are a critical concern in neonatal neurology.
- Brain energy metabolism, particularly phosphocreatine (PCr) levels, matures postnatally.
Purpose of the Study:
- To investigate the impact of creatine (Cr) on brain energy metabolism in developing rabbits.
- To determine if creatine supplementation can prevent seizures induced by hypoxia.
- To correlate brain energy status with seizure susceptibility during development.
Main Methods:
- Subcutaneous administration of creatine (3 g/kg) or saline to rabbit pups aged 5–30 days.
- Exposure to controlled hypoxia (4% O2 for 8 min) to induce seizures.
- In vivo 31P magnetic resonance spectroscopy (MRS) to measure brain phosphocreatine/nucleoside triphosphate (PCr/NTP) ratios in gray and white matter.
Main Results:
- Hypoxic seizures peaked in frequency at 15 and 20 days of age in control pups.
- Creatine treatment prevented seizures at 15 days and reduced them by 60% at 20 days.
- Creatine administration significantly increased brain PCr/NTP ratios across all ages and brain regions, reaching mature levels.
Conclusions:
- The maturation of brain energy metabolism, indicated by the PCr/NTP ratio, is closely linked to the development of seizure resistance.
- Systemic creatine supplementation enhances brain energy reserves and confers protection against hypoxic seizures in developing rabbits.
- Mature levels of brain phosphocreatine and/or creatine may be essential for limiting EEG activation and preventing metabolic disturbances during hypoxia.
Abstract:
To study the effects of creatine (Cr) on brain energy metabolism and on hypoxia-induced seizures, 5- to 30-day-old rabbit pups were given subcutaneous Cr (3 g/kg) for 3 days before exposure to 4% O2 for 8 min. In saline-treated controls, hypoxic seizures were most frequent at 15 days (80% of pups) and 20 days (60%) of age. Seizures were prevented at 15 days and reduced 60% at 20 days in Cr-treated pups. In surface coil-localized brain 31P nuclear magnetic resonance spectra, with signal from both cerebral gray (GM) and white (WM) matter, the phosphocreatine (PCr)/nucleoside triphosphate (NTP) ratio doubled between 5 and 30 days of age in controls. In all Cr-injected pups, brain PCr/NTP increased to values seen in 30-day-old controls. When spectra were acquired in predominantly GM and WM slices in vivo, the PCr/NTP ratio was very low in GM at 5 days but reached adult levels by 15 days in controls. In WM, the ratio increased steadily from 5 to 30 days of age. In Cr-injected pups, PCr/NTP increased to mature levels in WM and in GM at all ages. In conclusion, hypoxic seizures occur midway in the time course of brain PCr/NTP increase in rabbit pups as previously described in rat pups. In both altricial pups, systemic Cr increases brain PCr/NTP ratio and prevents hypoxic seizures. These results suggest that mature levels of PCr and/or Cr in brain limit EEG activation either directly or indirectly by preventing hypoxic metabolic changes.