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Secondary energy failure in a neonatal rat brain slice model

Presented at the Neonatal Society 2002 Summer Meeting (programme).

Robertson NJ, Bhakoo KK, Edwards AD, Cox IJ

Department of Paediatrics, Imperial College of Science, Technology and Medicine, Hammersmith Campus, DuCane Road, London, UK.

Background: Following perinatal hypoxia-ischaemia (HI) brain energetics apparently recover with resuscitation. Using magnetic resonance (MR) spectroscopy there is, however, a secondary decline in phosphocreatine (PCr)/inorganic phosphate (Pi), rise in cerebral lactate/creatine (Cr) and brain alkaline intracellular pH (pHi) from 6-8 hours following birth. The extent of these changes is closely related to the severity of brain injury and subsequent neurodevelopmental outcome (1). The brain slice model is an integral part of neuroscience research as the cytoarchitecture and neuronal/glial interaction are preserved but there are important metabolic differences to the in vivo brain. We hypothesised that the neonatal rat brain slice model itself demonstrates secondary energy failure (SEF), which is delayed with hypothermia (2).

Methods: 350 mm brain slices were prepared from 7 and 14-day Wistar rat pups. Slices were continuously perfused in oxygenated Krebs-Henseleit buffer (KHB) in a Jeol Eclipse+ 11.7T MR spectrometer and interleaved 1H and 31P MR spectra were obtained over 8 hours at 37șC (n=7) and at 32șC (n=8). The mean pHi and % change in mean PCr/Pi, lactate/NAA were calculated.

Results: The 7 and 14-day models demonstrated pHi heterogeneity and similar values of PCr/Pi and lactate/N-acetylaspartate (NAA) one hour after slicing. The metabolite ratio at 1 hour (time when stabilization occurred) was defined as 100% and subsequent ratios were then compared. PCr/Pi declined over 8 hours in both models and the rate of decline was similar in both the 7 and 14-day models. The PCr/Pi decline was delayed at 32șC. Lactate/NAA increased at 4 hours and plateaued; this increase in lactate/NAA was prevented at 32șC. Data from the 14-day model are shown.

Conclusions: The brain slice model demonstrated SEF over 8 hours in both the 7 and 14-day preparation and the energetic basis of neuroprotection with hypothermia was confirmed. Such a model may be of use in assessing the efficacy of other neuroprotective agents.

1. Azzopardi et al. Pediatr Res 1989;25:445-51.
2. Thoresen et al. Pediatr Res 1995;37:667-70.

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