Hypothermia is Neuroprotective after Severe Hypoxic-Ischaemic Brain Injury in neonatal rats pre-exposed to PAM3CSK4

Mari Falck, Damjan Osredkar, Elke Maes, Torun Flatebø, Thomas Wood, Lars Walløe, Hemmen Sabir, Marianne Thoresen

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Background: Pre-clinical research on the neuroprotective effect of hypothermia after perinatal asphyxia has shown variable results, depending on co-morbidities and insult severity. Exposure to inflammation increases vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury, and could be one explanation for those neonates whose injury is unexpectedly severe. Gram-negative type inflammatory pre-sensitisation with lipopolysaccharide (LPS) prior to a mild HI insult negates hypothermic neuroprotection. However, the neuroprotective effect of HT is fully maintained after gram-positive type pre-sensitisation with PAM3CSK4 (PAM) in the same HI model. Whether HT is neuroprotective in severe brain injury with gram-positive inflammatory pre-sensitisation has not been investigated.
Methods: 59 seven-day-old rat pups were subjected to a unilateral HI insult, with left carotid artery ligation followed by 90 min hypoxia (8% O2 at Trectal 36°C). An dditional 196 pups received intraperitoneal 0.9% saline (control) or PAM1mg/kg, 8 h before undergoing the same HI insult. After randomisation to 5 h normothermia (NT37°C) or HT32°C, pups survived one week before they were sacrificed by perfusion fixation. Brains were harvested for hemispheric (HEM) and ippocampal (HIP) area loss analyses at P14, as well as immunostaining for neuron count in the HIP CA1 region.
Results: Normothermic PAM animals (PAM-NT) had a comparable median area loss (HEM: 60% (95% CI 33-66); HIP: 61% (95% CI 29-67)) to vehicle animals (Veh-NT) (HEM: 58% (95% CI 11-64); HIP: 60% (95% CI 19-68)), which is defined as severe brain injury. Furthermore, mortality was low and similar in the two groups (Veh-NT 4.5% vs PAM-NT .6%). HT significantly reduced HEM and HIP injury in the Veh group (HEM: p=0.048; HIP: p=0.042) as well as in the PAM group (HEM: p=0.03; HIP: p=0.027).
Conclusion: In these experiments with severe brain injury, TLR-2 exposure prior to HI does not have an additive injurious effect, and there is a small but significant neuroprotective effect of HT. Hypothermia appears to be neuroprotective over a continuum of injury severity in this model, and the effect size tapers off with increasing area loss. Our results indicate that gram-1
positive inflammatory exposure prior to HI injury does not negate a neuroprotective effect of
HT in severe brain injury.
Original languageEnglish
Article number201710007
Number of pages9
JournalDevelopmental Neuroscience
Early online date1 Jun 2018
Publication statusE-pub ahead of print - 1 Jun 2018


  • PAM3CSK4
  • perinatal infection
  • maternal pyrexia
  • perinatal asphyxia
  • encephalopath
  • temperature, LPS

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