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Brain creatine kinase and creatine transporter proteins in normal and creatine-treated rabbit pups
T Kekelidze1, I Khait, A Togliatti
1Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. tkeke@bwh.harvrd.edu
Insights
Systemic creatine supplementation increases brain phosphocreatine, preventing seizures in young rabbits. This occurs due to increased phosphocreatine, not changes in creatine kinase enzymes or reaction rates.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Systemic creatine (Cr) supplementation is known to increase brain phosphocreatine (PCr) levels and protect against hypoxic seizures in developing rabbits.
- During normal development (5-30 days), significant increases in mitochondrial creatine kinase (Mi-CK) and cytosolic CK (BB-CK) occur in gray matter, with smaller increases in white matter.
- The creatine transporter protein concentration decreases substantially in both gray and white matter during this developmental period.
Purpose of the Study:
- To investigate the effects of systemic creatine supplementation on the creatine kinase (CK) system and phosphocreatine (PCr) levels in the developing rabbit brain.
- To determine if creatine supplementation alters the expression of CK isoenzymes (Mi-CK, BB-CK) or in vivo CK reaction rate constants.
- To understand the relationship between creatine supplementation, brain energy metabolism, and seizure protection.
Main Methods:
- Systemic creatine supplementation was administered to 15-day-old rabbits.
- Brain tissue (gray and white matter) was analyzed for levels of CK isoenzymes (Mi-CK, BB-CK) and creatine transporter protein.
- (31)P nuclear magnetic resonance was used to measure in vivo CK reaction rate constants in brain slices.
- Hypoxic seizures were induced to assess the protective effects of creatine.
Main Results:
- Systemic creatine supplementation significantly increased brain phosphocreatine (PCr) levels in both gray and white matter.
- Creatine supplementation did not significantly alter the levels of Mi-CK or BB-CK isoenzymes or the in vivo CK reaction rate constants.
- The primary change observed in the CK system following creatine treatment was the elevated PCr concentration, correlating with seizure suppression.
Conclusions:
- Systemic creatine supplementation effectively increases brain phosphocreatine levels in developing rabbits, providing protection against hypoxic seizures.
- The seizure-protective effect of creatine appears to be mediated by increased PCr availability rather than alterations in CK enzyme activity or expression.
- These findings highlight the importance of the creatine-PCr energy buffering system in the developing brain and its potential therapeutic role in conditions involving energy deficits.
Abstract:
Systemic creatine (Cr) supplementation increases brain phosphocreatine (PCr) and prevents hypoxic seizures in 15-day-old rabbits. Between 5 and 30 days of age during normal development, rabbit gray matter mitochondrial creatine kinase (Mi-CK) increases 400% while cytosolic CK (BB-CK) increases 60%. In white matter, both isoenzymes show smaller, similar increases (40%) during this period. The Cr transporter protein decreases 60% between 5 and 15 days in both regions. In vivo CK rate constants measured by (31)P nuclear magnetic resonance increase 30% between 10 and 20 days, and then fall 50% between 20 and 30 days in predominantly gray matter slices. Similar maturational changes are seen in predominantly white matter slices. Injecting Cr at 15 days does not significantly change BB-CK or Mi-CK isoenzymes or the in vivo CK reaction rate constants. Thus, the largest change in the CK system associated with suppression of hypoxic seizures in Cr-treated rabbits is increased PCr in gray and white matter.