The
creatine-
phosphocreatine shuttle is essential for the maintenance of cellular
ATP, particularly under hypoxic conditions when respiration may become anaerobic. Using a model of intrapartum
hypoxia in the precocial spiny mouse (Acomys cahirinus), the present study assessed the potential for maternal
creatine supplementation during pregnancy to protect the developing brain from the effects of birth
hypoxia. On day 38 of gestation (term is 39 days), the pregnant uterus was isolated and placed in a saline bath for 7.5 min, inducing global
hypoxia. The pups were then removed, resuscitated, and cross-fostered to a nursing dam. Control offspring were delivered by
caesarean section and recovered immediately after release from the uterus. At 24 h after birth
hypoxia, the brains of offspring from dams fed a normal diet showed significant increases in lipid peroxidation as measured by the amount of
malondialdehyde. In the cortical subplate, thalamus and piriform cortex there were significant increases in cellular expression of the
pro-apoptotic protein BAX, cytoplasmic
cytochrome c and
caspase-3. When pregnant dams were fed the
creatine supplemented diet, the increase in
malondialdehyde, BAX,
cytochrome c and
caspase 3 were almost completely prevented, such that they were not different from control (caesarean-delivered) neonates. This study provides evidence that the neuroprotective capacity of
creatine in the hypoxic perinatal brain involves abrogation of lipid peroxidation and apoptosis, possibly through the maintenance of mitochondrial function. Further investigation into these mechanisms of protection, and the long-term development and behavioural outcomes of such neonates is warranted.