期刊
DEVELOPMENTAL NEUROSCIENCE
卷 39, 期 1-4, 页码 238-247出版社
KARGER
DOI: 10.1159/000455838
关键词
Perinatal brain injury; Asphyxia; Hypothermia therapy; Neuroprotection; Infection; Inflammation; Gram-positive pathogens; PAM(3)CSK(4); Lipopolysaccharide
资金
- Norwegian Research Council [NFR 214356/F20]
Perinatal infection increases the vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury. Hypothermia treatment (HT) does not provide neuroprotection after pre-insult inflammatory sensitisation by lipopolysaccharide (LPS), a gram-negative bacterial wall constituent. However, earlyonset sepsis in term babies is caused by gram-positive species in more than 90% of cases, and neuro-inflammatory responses triggered through the gram-negative route (Toll-like receptor 4, TLR-4) are different from those induced through the gram-positive route via TLR-2. Whether gram-positive septicaemia sensitises the neonatal brain to hypoxia and inhibits the neuroprotective effect of HT is unknown. Seven-day-old Wistar rats (n = 178) were subjected to intraperitoneal injections of PAM 3 CSK 4 (1 mg/kg, a synthetic TLR-2 agonist) or vehicle (0.9% NaCl). After an 8-h delay, the left carotid artery was ligated followed by 50 min of hypoxia (8% O-2) at a rectal temperature of 36 degrees C. Pups received a 5-h treatment of normothermia (NT, 37 degrees C) or HT (32 degrees C) immediately after the insult. Brains were harvested after 7 days' survival for hemispheric and hippocampal area loss analyses and immunolabelling of microglia (Iba1) and hippocampal neurons (NeuN). Normothermic PAM(3)CSK(4)-injected animals showed significantly more brain injury than vehicle animals (p = 0.014). Compared to NT, HT significantly reduced injury in the PAM(3)CSK(4)-injected animals, with reduced area loss (p < 0.001), reduced microglial activation (p = 0.006), and increased neuronal rescue in the CA1 region (p < 0.001). Experimental induction of a sepsis-like condition through the gram-positive pathway sensitises the brain to HI injury. HT was highly neuroprotective after the PAM(3)CSK(4)-triggered injury, suggesting HT may be neuroprotective in the presence of a gram- positive infection. These results are in strong contrast to LPS studies where HT is not neuroprotective. (C) 2017 S. Karger AG, Basel
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