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Chronobiology in Neonatal Encephalopathy

Presented at the Neonatal Society 2018 Summer Meeting.

O’Dea M1,2,3,4,5, Strickland T1,2, Kelly L1,2,3, Molloy EJ1,2,3,4,5,6

1 Discipline of Paediatrics and Child Health, Trinity College Dublin
2 Trinity Translational Medicine Institute, St James Hospital
3 Coombe Women and Infant’s University Hospital
4 National Maternity Hospital, Dublin
5 National Children’s Hospital, Tallaght
6 Our Lady’s Children’s Hospital, Crumlin

Background: In Neonatal Encephalopathy (NE) – a complex and devastating brain condition mediated by systemic inflammation – the earlier acquisition of a normal sleep-wake cycle is associated with better outcomes. The immune system demonstrates functional changes with time of day and the disruption of circadian rhythms has been linked to inflammatory disorders. Further understanding of chronobiology in NE has important implications for future therapeutic targets. Hypothesis; To evaluate the expression of circadian genes in NE at baseline and following endotoxin (LPS) stimulation in comparison to healthy term controls (TCs), and to correlate the circadian rhythm with the infants outcome; survival and neuroimaging

Methods: Quantitative RT PCR analysis of BMAL, CLOCK, CRY and REV-ERB β in NEs (n=12) was compared to TCs (n=8) at baseline and in response to LPS stimulation. Inflammatory phenotype was measured via serum ELISA analysis. Ethical Approval and Parental Consent were obtained. The Research was funded by the Health Research Board.

Results: BMAL, CLOCK and REV-ERB β were increased in NE day 1 (1.7, 1.2 and 1.7 fold) and on day 3 (1.8, 1.4 and 1.3 fold) at baseline compared to TCs. CLOCK and REV-ERB β were significantly downregulated in response to LPS stimulation in NE on day 1, while BMAL, CLOCK and REV-ERB β were significantly downregulated on day 3 (all p<0.05). Pro inflammatory IL-2 was negatively correlated with BMAL in NE, and positively correlated with CLOCK, CRY & Reverb B. Pro Inflammatory IL-1 Beta was positively correlated with CLOCK. Pro inflammatory IFN-y and IL-6 were positively correlated with REV-Erb β. Hypoxia mediator EPO was positively correlated with CRY. There were no neonatal deaths in the cohort. There were no differences in the chronobiology in patients with normal in comparison to abnormal neuroimaging.

Conclusion: Circadian genes are highly expressed in NE at baseline and are downregulated in response to LPS stimulation. This trend may help to explain the altered innate immunity observed in NE. Manipulation of the chronobiology in NE may represent a novel therapeutic opportunity.

Corresponding author: tstrickl@tcd.ie

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