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Dual action of melatonin on neonatal rat brain following an inflammatory challenge

Presented at the Neonatal Society 2016 Summer Meeting.

Favrais G1,2, Silvia C3, Chalon S2, Gressens P41, Buonocore G5, Saliba E1,2

1 Neonatal Intensive care Unit, University Hospital of Tours, Tours, France
2 INSERM U930, François Rabelais University, Tours , France
3 Biomolecular Sciences Department, Urbino, Italy
4 INSERM U1141, Diderot university, Paris, France
5 Molecular and Developmental Medecine, Siena, Italy

Background: Developmental brain is particularly vulnerable to hypoxic-ischemic and inflammatory insults. Melatonin demonstrated neuroprotective properties on hypoxic ischemic lesions. The aim was to test the melatonin ability to modulate inflammatory stress induced in pregnant rats and its consequences on the litter brain myelination and on the size of a secondary excitotoxic brain lesion.

Methods: Pregnant rats were intraperitoneally injected at G19 and G20 with either saline solution or LPS 300 μg/kg or melatonin 5 mg/kg or LPS plus melatonin. Pup brains were collected at postnatal day (PND) 1, 7 and 21 for immunofluorescence and molecular biology (Western blot and PCR) analysis. Pup sera were harvested at PND 1 to dose systemic cytokines. A second excitatory insult was performed at PND 4 and the brain lesion size induced was measured in each experimental group. Experimental procedure has been approved by the “Val de Loire” ethical Committee (n° 00022.01).

Results: LPS injections had a sensitization effect on excitotoxic brain lesion which is completely prevent by melatonin co-injections. Furthermore, melatonin significantly reduced systemic and brain inflammation induced by LPS at PND 1. One mechanism underlying this protective effect in inflammatory context was a prevention of LPS-induced endoplasmic reticulum stress and a restoration of autophagic process through the SIRT-1 pathway. Surprinsingly, melatonin failed to prevent the reduction of pup number per litter and the decrease of pup birth weight induced by LPS. In parallel, the transient hypomyelination observed at PND 7 in LPS group was also present in LPS plus melatonin group.

Conclusion: Melatonin modulates inflammatory stress to prevent lesional brain event. However, melatonin action on developmental effect of inflammation on brain myelination is less obvious. A temporal window of susceptibility and the timing of melatonin injection regarding the inflammatory challenge could be hypothesis to explore.

Corresponding author: g.favrais@chu-tours.fr

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