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Classical Neuropathology Shows Hypothermic Neuroprotection In Seven Day Old Rats After A Mild A Hypoxic Ischemic Insult

Authors
Julia K. Gundersen, Else Marit Løberg, Damjan Osredkar, Mari Falck, Thomas R Wood, Lars Walløe,
Marianne Thoresen

Institution(s): Division of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway 2. Department of Pathology, Oslo University Hospital, Ullevål, University of Oslo, Oslo, Norway 3.Translational Health Sciences, St. Michael’s Hospital, University of Bristol, Bristol, UK

Introduction
It is unknown whether infants with mild hypoxic ischaemic encephalopathy (HIE) benefit from therapeutic hypothermia (TH), hence we examined this in a mild (50min 8%O2@36°C) rat model of neonatal brain injury. Previously, we demonstrated 30% neuroprotection from TH after a moderate insult (90min 8%O2@36°C). TH was not neuroprotective after a severe HI insult (150min 8%O2@37°C). We aimed to examine, which analysis method, computerized area loss calculations or classical neuropathology scoring, most reliably quantified mild injury.

Methods
7 day-old rats (n=73) underwent left carotid artery ligation followed by 50min of hypoxia (8%O2@36°C). Pups were randomised to 5h NT 37°C (n=36) or 5h TH 32°C (n=37) followed by 1 week survival. Haematoxylin-Eosin stained slides from 2 sections per animal were assessed for injury using both; 1) ImageJ software calculated percent global area loss in the ligated hemisphere relative to the unligated hemisphere, 2) regional neuropathology scoring from 0.0-4.0 (0.5 increments) of the hippocampus, cortex, thalamus and basal ganglia. The average of all regions was calculated as the global pathology. The non-parametric Wilcoxon-van-Elteren test was used.

Results
ImageJ analysis of global (%) area loss did not show significant differences between treatments: (median, 95% CI) 5h NT 8.4% (4.9-17.9) and 5h TH 5.8% (3.7-9.2), p=0.09, two-sided testing.

Fig. 1 shows the distribution in pathology score in the 4 brain regions (median, 95% CI) in both treatment groups.

TH showed significant neuroprotective effect on global neuropathology (median, 95% CI): NT 0.4 (0.0-1.06) and TH 0.0 (0.0-0.56), p=0.04.

Conclusions
By assessing the brain sections with classical neuropathology scoring, we demonstrated global neuroprotection by TH after a mild (~10%) HI insult. In experiments with mild insults, a sensitive method of identifying injury is required to more accurately demonstrate group differences. Our experimental findings support the hypothesis that immediate TH is beneficial after mild neonatal hypoxic-ischaemic brain injury.

References
Thoresen M et al Arch Dis Child Fetal Neonatal Ed. 1996;74(1):F3-9. Bona E et al Pediatr Res. 1998;43(6):738-45. Sabir H et al Stroke. 2012;43(12):3364-70.

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