Comparison of Three Hypothermic Target Temperatures for the Treatment of Hypoxic Ischemia: mRNA Level Responses of Eight Genes in the Piglet Brain
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Hypothermia can reduce neurodevelopmental disabilities in asphyxiated newborn infants. However, the optimal cooling temperature for neuroprotection is not well defined. We studied the effects of transient piglet brain hypoxic ischemia (HI) on transcriptional activity of eight genes and if mRNA level alterations could be counteracted by whole body cooling to 35, 33.5 or 30 °C. BDNF mRNA was globally upregulated by the insult, and none of the cooling temperatures counteracted this change. In contrast, MANF mRNA was downregulated, and these changes were modestly counteracted in different brain regions by hypothermic treatment at 33.5 °C, while 30 °C aggravated the MANF mRNA loss. MAP2 mRNA was markedly downregulated in all brain regions except striatum, and cooling to 33.5 °C modestly counteract this downregulation in the cortex cerebri. There was a tendency for GFAP mRNA levels in core, but not mantle regions to be downregulated and for these changes to be modestly counteracted by cooling to 33.5 or 35 °C. Cooling to 30 °C caused global GFAP mRNA decrease. HSP70 mRNA tended to become upregulated by HI and to be more pronounced in cortex and CA1 of hippocampus during cooling to 33.5 °C. We conclude that HI causes alterations of mRNA levels of many genes in superficial and deep piglet brain areas. Some of these changes may be beneficial, others detrimental, and lowering body temperature partly counteracts some, but not all changes. There may be general differences between core and mantle regions, as well as between the different cooling temperatures for protection. Comparing the three studied temperatures, cooling to 33.5 °C, appears to provide the best cooling temperature compromise.
KeywordsNeonatal asphyxia Hypoxic ischemic encephalopathy Therapeutic hypothermia Neuronal and glial markers In situ hybridisation Piglets
We thank Eva Lindqvist and Karin Pernold for the excellent technical support. This study is supported by the Märtha Lundqvist stiftelse (LO), The Swedish Research Council (HL, LO, DG), Stiftelsen Barncentrum (LO), The British MRC (NR), Karolinska Institutet, The Karolinska Distinguished Professor Award (LO), and Swedish Brain Power (LO, DG). The preparation of piglets until sacrifice and administration of hypothermia was undertaken at UCLH/UCL, with funding from the United Kingdom Department of Health’s NIHR Biomedical Research Centres (NR). In situ hybridization for lactate dehydrogenases is supported by the National Institute on Aging, NIH (AG04418), and in situ hybridization for plasticity genes (BDNF and NgR) is supported by the National Institute on Drug Abuse, NIH (LO).
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