Melatonin Promotes Oligodendroglial Maturation of Injured White Matter in Neonatal Rats

Paul Olivier,Véronique Massonneau,Jeremie Dalous,Olivier Baud,Gauthier Loron,Juliette Van Steenwinckel,Marie-Stéphane Aigrot,Pierre Gressens,Julien Pansiot,Angela Kaindl,Christiane Charriaut-Marlangue,Catherine Verney,Romain H Fontaine,Valérie Biran,Kenji Hashimoto

doi:10.1371/journal.pone.0007128

Abstract

ObjectiveTo investigate the effects of melatonin treatment in a rat model of white matter damage (WMD) in the developing brain. Additionally, we aim to delineate the cellular mechanisms of melatonin effect on the oligodendroglial cell lineage.MethodsA unilateral ligation of the uterine artery in pregnant rat at the embryonic day 17 induces fetal hypoxia and subsequent growth restriction (GR) in neonatal pups. GR and control pups received a daily intra-peritoneal injection of melatonin from birth to post-natal day (P) 3.ResultsMelatonin administration was associated with a dramatic decrease in microglial activation and astroglial reaction compared to untreated GR pups. At P14, melatonin prevented white matter myelination defects with an increased number of mature oligodendrocytes (APC-immunoreactive) in treated GR pups. Conversely, melatonin was not found to be associated with an increased density of total oligodendrocytes (Olig2-immunoreactive), suggesting that melatonin is able to promote oligodendrocyte maturation but not proliferation. These effects appear to be melatonin-receptor dependent and were reproduced in vitro.InterpretationThese data suggest that melatonin has a strong protective effect on developing damaged white matter through decreased microglial activation and oligodendroglial maturation leading to a normalization of the myelination process. Consequently, melatonin should be a considered as an effective neuroprotective candidate not only in perinatal brain damage but also in inflammatory and demyelinating diseases observed in adults.

Highlights

Brain injury and subsequent neurodevelopmental disabilities resulting from premature birth are a major public health concern
Systemic treatment using 20 mg/kg/d melatonin given within the first 3 postnatal days was associated with a significant 58% attenuation of myelination defects detected in the cingulate white matter in P14 growth restriction (GR) pups (p,0.001) (Figures 1A–E)
For birth weights greater than 4.5 g, the melatonin treatment was associated with a remarkably stabilized MBP density regardless the birth weight, in contrast to untreated animals in which myelin content appeared closely correlated with birth weight (Figure 1F)

Summary

Introduction

Brain injury and subsequent neurodevelopmental disabilities resulting from premature birth are a major public health concern. The most prominent neuropathological lesion is diffuse white matter damage (WMD) showing an association of glial injury together with microglial activation and, myelination defects. Many factors are associated with WMD, including: infection, hypoxia, ischemia, endocrine imbalances, genetic factors and growth restriction [1,2,3]. Intra uterine growth retardation (IUGR) has been shown to be associated with both white matter lesions and subsequent neurological impairment [4,5,6] Based on these potential targets, a number of treatments for neonatal brain injury including melatonin have been investigated [7]

Methods

Results

Conclusion