Melatonin Promotes Oligodendroglial Maturation of Injured White Matter in Neonatal Rats

• DOI: 10.1371/journal.pone.0007128
• Publication Date: 2009-09-21T18:20:54Z
• Authors: Paul Olivier; Romain H. Fontaine; Gauthier Loron; Juliette Van Stee...; Valérie Biran; Véronique Massonneau; Angela Kaindl; Jeremie Dalous; Christiane Charri...; Marie-Stéphane Ai...; Julien Pansiot; Catherine Verney; Pierre Gressens; Olivier Baud
• Keywords: Time Factors; Cells; Science; Messenger; 610; Nerve Fibers, Myelinated; Fluorescence; Rats, Sprague-Dawley; 03 medical and health sciences; Nerve Fibers; Animals; Developmental; Cell Lineage; RNA, Messenger; Cells, Cultured; Melatonin; Microscopy; 0303 health sciences; Cultured; Q; R; Brain; Gene Expression Regulation, Developmental; Newborn; Immunohistochemistry; Rats; 3. Good health; Oligodendroglia; Gene Expression Regulation; Animals, Newborn; Microscopy, Fluorescence; Myelinated; RNA; Medicine; Sprague-Dawley; Research Article

To 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.A 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.Melatonin 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.These 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.