Creatine protects the immature brain from hypoxic-ischemic injury.
OBJECTIVE
We tested the neuroprotective effects of creatine against hypoxic-ischemic injury in the 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 the start 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 infarction, 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 the frontal level (A 6.0 mm), neuronal cell injury was significantly lower in the cortex of the animals that had received creatine. This was also true for the evaluated subfields in the hippocampus.


CONCLUSIONS
We conclude that creatine protects the immature brain from hypoxic-ischemic injury.
Berger
Richard
R
Department of Obstetrics and Gynecology, University of Bochum, Bochum, Germany. richard.berger@ruhr-uni-bochum.de
Middelanis
Johannes
J
Vaihinger
Hans-Martin
HM
Mies
Guenter
G
Wilken
Bernd
B
Jensen
Arne
A
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects*; D003401:Creatine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005865:Gestational Age; D005947:Glucose / Q000008:administration & dosage; D006168:Guinea Pigs; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000196:embryology; D020925:Hypoxia-Ischemia, Brain / Q000517:prevention & control*; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D010100:Oxygen / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar
D009419:Nerve Tissue Proteins; D000255:Adenosine Triphosphate; D005947:Glucose; D003401:Creatine; D010100:Oxygen