A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia.

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.

Effects of birth asphyxia on neonatal hippocampal structure and function in the spiny mouse.

Studies of human neonates, and in animal experiments, suggest that birth asphyxia results in functional compromise of the hippocampus, even when structural damage is not observable or resolves in early postnatal life. The aim of this study was to determine if changes in hippocampal function occur in a model of birth asphyxia in the precocial spiny mouse where it is reported there is no major lesion or infarct. Further, to assess if, as in human infants, this functional deficit has a sex-dependent component. At 37 days gestation (term=39 days) spiny mice fetuses were either delivered immediately by caesarean section (control group) or exposed to 7.5min of in utero asphyxia causing systemic acidosis and hypoxia. At 5 days of age hippocampal function was assessed ex vivo in brain slices, or brains were collected for examination of structure or protein expression. This model of birth asphyxia did not cause infarct or cystic lesion in the postnatal day 5 (P5) hippocampus, and the number of proliferating or pyknotic cells in the hippocampus was unchanged, although neuronal density in the CA1 and CA3 was increased. Protein expression of synaptophysin, brain-derived neurotrophic factor (BDNF), and the inositol trisphosphate receptor 1 (IP(3)R1) were all significantly increased after birth asphyxia, while long-term potentiation (LTP), paired pulse facilitation (PPF), and post-tetanic potentiation (PTP) were all reduced at P5 by birth asphyxia. In control P5 pups, PPF and synaptic fatigue were greater in female compared to male pups, and after birth asphyxia PPF and synaptic fatigue were reduced to a greater extent in female vs. male pups. In contrast, the asphyxia-induced increase in synaptophysin expression and neuronal density were greater in male pups. Thus, birth asphyxia in this precocial species causes functional deficits without major structural damage, and there is a sex-dependent effect on the hippocampus. This may be a clinically relevant model for assessing treatments delivered either before or after birth to protect this vulnerable region of the developing brain.