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Limb Remote Ischemic Post-Conditioning Protects Cerebral White Matter in a Piglet Model of Perinatal Asphyxia

Presented at the Neonatal Society 2015 Spring Meeting.

Ezzati M1, Broad KD1, Kawano G1, Ferreira ER1, Alconada DA1, Fierens I1, Rostami J1, Hassell J1, Tachtsidis I2, Gressens P3,4, Fleiss B3,4, Yellon D5, Hausenloy DJ5, Golay X6, Robertson NJ1

1 Institute for Women’s Health, University College London
2 Medical Physics and Biomedical Engineering, University College London
3 Department of Perinatal Imaging and Health, King’s College London
4 Inserm, U1141, Paris
5 The Hatter Cardiovascular Institute, University College London
6 Institute of Neurology, University College London

Background: Despite therapeutic hypothermia, ~ 50% treated babies have adverse outcomes; additional simple, safe, effective treatments are needed. Ischaemic postconditioning is a powerful innate protective mechanism against ischaemic-reperfusion injury (1). We aimed to determine if remote ischaemic postconditioning (RIPostC) after cerebral hypoxia-ischaemia (HI) is neuroprotective in a piglet model.

Methods: UK Home Office Guidelines [Animals (Scientific procedures) Act, 1986] (MRC grant MR/J00457X/1). After HI, randomisation to: (i) No intervention (n=8); or (ii) RIPostC – four 10 minute cycles of bilateral lower limb ischaemia/reperfusion immediately after HI (n=8). Magnetic resonance spectroscopy was acquired at 24 & 48 h; assessment of regional cell death by immunohistochemistry and gene expression by microarray and qPCR.

Results: Cerebral white matter protection was seen with four 10 minute cycles of hind-limb ischaemia/reperfusion, evidenced by improved brain energy metabolism at 48h with reduced lactate/N-acetyl aspartate in white matter (p=0.005) and increased NTP/exchangeable phosphate pool (p=0.039). On immunohistochemistry, cell death was reduced in periventricular white matter (PvWM) (p=0.03), internal capsule (p=0.002) and corpus callosum (CC) (p=0.021); there was reduced microglial activation in the CC (p=0.001) and higher numbers of surviving oligodendrocytes in the CC (0.029) and PvWM (p=0.001). Changes in gene expression included the ATP-sensitive potassium channel and endothelin A receptor, changes previously seen with RIPostC protection. Phosphorylated ERK activity was increased in the white matter, indicating activation of pro-survival cell pathways.

Conclusion: Four cycles of 10 minute hind limb ischaemia /reperfusion immediately after cerebral hypoxia-ischaemia protected cerebral white matter. RIPostC was well tolerated and simple to perform. Such a degree of protection is likely to translate into a meaningful clinical effect; further studies are needed.

Corresponding author: n.robertson@ucl.ac.uk

References
1. Pignataro et al., In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: ischaemic post conditioning. J Cereb Blood Flow Metab 2008:28(2):232-41.

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