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Hypothermic Neuronal Rescue from Infection-sensitised Hypoxic-Ischaemic Brain Injury is Pathogen Dependent

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)238-247
Number of pages10
JournalDevelopmental Neuroscience
Issue number1-4
Early online date14 Apr 2017
DateAccepted/In press - 6 Jan 2017
DateE-pub ahead of print - 14 Apr 2017
DatePublished (current) - 2017


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, early-onset 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 (P7) Wistar rats (n=178) were subjected to intraperitoneal injections of PAM3CSK4 (1 mg/kg, a synthetic TLR-2 agonist) or vehicle (0.9% NaCl). After an 8-hour delay, the left carotid artery was ligated followed by 50min of hypoxia (8% O2) at Trectal36°C. Pups received 5h treatment of normothermia (NT, 37°C) or HT (32°C) immediately after the insult. Brains were harvested after seven days’ survival for hemispheric and hippocampal area loss analyses and immunolabelling of microglia (Iba1) and hippocampal neurons (NeuN). Normothermic PAM3CSK4-animals showed significantly more brain injury than vehicle animals (p=0.014). Compared to NT, HT significantly reduced injury in the PAM3CSK4-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. HT was highly neuroprotective after the PAM3CSK4-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.

    Research areas

  • Perinatal brain injury, Asphyxia, Hypothermia therapy, Neuroprotection, Infection, Inflammation, Gram-positive, PAM3CSK4, LPS

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Karger at Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 318 KB, PDF document


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