Abstract
To improve the understanding of the molecular mechanisms whereby lipopolysaccharide (LPS) affects the immature brain, global gene expression following LPS exposure was investigated in neonatal rats. Brains (n = 5/time point) were sampled 2, 6, and 72 h after LPS and compared with age-matched controls. The mRNA from each brain was analyzed separately on Affymextrix GeneChip Rat Expression Set 230. The number of genes regulated after LPS were 847 at 2 h, 1564 at 6 h, and 1546 genes at 72 h. Gene ontology analysis demonstrated that, at both 2 and 6 h after LPS, genes associated with protein metabolism, response to external stimuli and stress (immune and inflammatory response, chemotaxis) and cell death were overrepresented. At 72 h, the most strongly regulated genes belonged to secretion of neurotransmitters, transport, synaptic transmission, cell migration, and neurogenesis. Several pathways associated with cell death/survival were identified (caspase-tumor necrosis factor α [TNF-α]-, p53-, and Akt/phosphatidylinositol-3-kinase (PI3 K)–dependent mechanisms). Caspase-3 activity increased and phosphorylation of Akt decreased 8 h after peripheral LPS exposure. These results show a complex cerebral response to peripheral LPS exposure. In addition to the inflammatory response, a significant number of cell death-associated genes were identified, which may contribute to increased vulnerability of the immature brain to hypoxia-ischemia (HI) following LPS exposure.
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Abbreviations
- FAIM2:
-
fas apoptotic inhibitory molecule 2
- HI:
-
hypoxia-ischemia
- LPS:
-
lipopolysaccharide
- NF-κB:
-
nuclear factor-κB
- pAkt:
-
phosphorylated Akt
- PHLDA1:
-
pleckstrin homology-like domain, member 1
- PI3 K:
-
phosphatidylinositol-3-kinase
- PKB:
-
protein kinase B
- PND:
-
postnatal day
- RMA:
-
robust multiarray average
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This work was supported by the Swedish Medical Research Council (K2004-33X-14185-03A and K2004-33X-09455), the Åhlén Foundation, the Sven Jerring Foundation, the Magnus Bergvall Foundation, the Wilhelm and Martina Lundgren Foundation, the Linnéa and Josef Carlsson Foundation, the Frimurare Barnhus Foundation, the Göteborg Medical Society, and the Åke Wibergs Foundation and by grants to researchers in the public health service from the Swedish government (ALF).
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Eklind, S., Hagberg, H., Wang, X. et al. Effect of Lipopolysaccharide on Global Gene Expression in the Immature Rat Brain. Pediatr Res 60, 161–168 (2006). https://doi.org/10.1203/01.pdr.0000228323.32445.7d
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DOI: https://doi.org/10.1203/01.pdr.0000228323.32445.7d
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