Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

Mari Falck, Damjan Osredkar, Elke Maes, Torun Flatebø, Thomas Ragnar Wood, Hemmen Sabir, Marianne Thoresen
2017 Developmental Neuroscience  
General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: 26 Perinatal infection increases the vulnerability of the neonatal brain to hypoxic-ischaemic (HI) 1 injury. Hypothermia Treatment (HT) does not provide neuroprotection after pre-insult 2 inflammatory sensitisation by lipopolysaccharide (LPS), a gram-negative bacterial wall 3 constituent. However, early-onset
more » ... er, early-onset sepsis in term babies is caused by gram-positive species 4 in more than 90 % of cases, and neuro-inflammatory responses triggered through the gram-5 negative route (toll-like receptor 4; TLR-4), are different from those induced through the 6 gram-positive route via TLR-2. Whether gram-positive septicaemia sensitises the neonatal 7 brain to hypoxia and inhibits the neuroprotective effect of HT is unknown. 8 Seven-day-old (P7) Wistar rats (n=178) were subjected to intraperitoneal injections of 9 PAM3CSK4 (1 mg/kg, a synthetic TLR-2 agonist) or vehicle (0.9% NaCl). After an 8-hour 10 delay, the left carotid artery was ligated followed by 50min of hypoxia (8% O2) at Trectal36°C. 11 Pups received 5h treatment of normothermia (NT, 37°C) or HT (32°C) immediately after the 12 insult. Brains were harvested after seven days' survival for hemispheric and hippocampal 13 area loss analyses and immunolabelling of microglia (Iba1) and hippocampal neurons 14 (NeuN). Normothermic PAM3CSK4-animals showed significantly more brain injury than 15 vehicle animals (p=0.014). Compared to NT, HT significantly reduced injury in the 16 PAM3CSK4-injected animals, with reduced area loss (p<0.001), reduced microglial activation 17 (p=0.006), and increased neuronal rescue in the CA1 region (p<0.001). Experimental 18 induction of a sepsis-like condition through the gram-positive pathway sensitises the brain to 19 HI. HT was highly neuroprotective after the PAM3CSK4-triggered injury, suggesting HT may 20 be neuroprotective in the presence of a gram-positive infection. These results are in strong 21 contrast to LPS-studies where HT is not neuroprotective. 22
doi:10.1159/000455838 pmid:28407632 fatcat:4npcgfd35nevhe42a7us37jgdi