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Creatine Protects the Immature Brain From Hypoxic-Ischemic Injury

Department of Obstetrics and Gynecology, University of Bochum, Bochum, Department of Experimental Neurology, Max-Planck-Institute for Neurological Research, Cologne, and Department of Pediatrics and Neuropediatrics, University of Göttingen, Göttingen, Germany richard.berger{at}ruhr-uni-bochum.de

Johannes Middelanis, MD

Hans-Martin Vaihinger, MSc

Guenter Mies, MD

Bernd Wilken, MD

Arne Jensen, MD

Department of Obstetrics and Gynecology, University of Bochum, Bochum, Department of Experimental Neurology, Max-Planck-Institute for Neurological Research, Cologne, and Department of Pediatrics and Neuropediatrics, University of Göttingen, Göttingen, Germany

Objective: We tested the neuroprotective effects of creatine against hypoxic-sichemic injury in hte immature brain.

Methods: Hippocampal slices were prepared from fetal guinea pigs at 0.9 gestation and incubated in artificial cerebrospinal fluid (aCSF) equilibrated with carbogen. Slices were subjected to oxygen-glucose deprivation (OGD) for 30 or 40 minutes. Two hours after OGD, adenosine triphosphate (ATP) and protein synthesis were analyzed. Creatine (3 mM) was applied to tissue slices of the study groups 2 hours before the insult. In a second set of experiments 7-day-old Wistar rats were anesthetized, and the left carotid artery was ligated. After 1 hour of recovery the pups were subjected to a hypoxic gas mixture (8% oxygen and 92% nitrogen) for 80 minutes. Seven days later the brains of the neonates were removed and analyzed for hypoxic-ischemic injury. The rat pups of the test group were treated with creatine (3 g/kg subcutaneously) before (-64 hours, -40 hours, and -16 hours) and after (+3 hours) the hypoxic-ischemic insult, with zero time corresponding to thes tart of hypoxia, whereas the animals of the control group received the solvent.

Results: Creatine significantly improved the recovery of protein synthesis 2 hours after OGD in hippocampal slices but had no effect on ATP levels. Whereas seven animals of the control group developed severe cystic cerebral infraction, only mild to moderate damage was observed in the rat pups of the study group. In contrast to creatine-treated pups, the volume of the ipsilateral hemisphere was considerably smaller than that of the contralateral one in control animals (104 ± 22 versus 138 ± 14 mL, P < .001). Except at had received cratine. This was also true for the evaluated subfileds in the hippocampus.

Conclusion: We conclude that creatine potects the immature brain from hypoxic-ischemic injury.

Key Words: Cretine • neuroprotection • brain • hippocampus • ischemia • htpoxia

Journal of the Society for Gynecologic Investigation, Vol. 11, No. 1, 9-15 (2004)
DOI: 10.1016/j.jsgi.2003.07.002


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