Melatonin promotes oligodendroglial maturation of injured white matter in neonatal rats.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Olivier
Paul
P
INSERM, AVENIR R05230HS, Hôpital Robert Debré, Paris, France.
Fontaine
Romain H
RH
Loron
Gauthier
G
Van Steenwinckel
Juliette
J
Biran
Valérie
V
Massonneau
Véronique
V
Kaindl
Angela
A
Dalous
Jeremie
J
Charriaut-Marlangue
Christiane
C
Aigrot
Marie-Stéphane
MS
Pansiot
Julien
J
Verney
Catherine
C
Gressens
Pierre
P
Baud
Olivier
O
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000196:embryology / Q000254:growth & development; D019070:Cell Lineage; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry / Q000379:methods; D008550:Melatonin / Q000378:metabolism / Q000502:physiology*; D008856:Microscopy, Fluorescence / Q000379:methods; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D012333:RNA, Messenger; D008550:Melatonin