Melatonin Promotes Oligodendroglial Maturation of Injured White Matter in Neonatal Rats

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.

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

“…Although this signaling pathway is an important regulator of morphological neuroplasticity (Negishi and Katoh, 2005), agomelatine was strikingly poor in reversing the maladaptive structural (and behavioral) alterations induced by uCMS. In silico analysis predicted that agomelatine acts on neurons and oligodendrocytes, matching previous observations that melatonin promotes oligodendroglial maturation (Olivier et al, 2009). …”

Melatonin Promotes Myelination by Decreasing White Matter Inflammation After Neonatal Stroke

“…It was suggested that the main target of melatonin treatment could be the maturation process of the oligodendrocyte lineage (13). Conversely, assuming that the cingulate myelination deficit was associated with focal cingulate microglial activation in our stroke model, and that immature oligodendrocytes are highly vulnerable in this inflammatory context (19) as, it is reasonable to hypothesize that melatonin could restore normal oligodendrocyte functions through a reduction in white matter inflammation.…”

“…1E). Because melatonin is recognized to combine antioxidant and anti-inflammatory properties (13,24), we asked the question whether this molecule could induce neuroprotection of the injured cortex and/or white matter by modulating this inflammatory response.…”

“…Immunoreactive cells were counted in the ipsilateral and contralateral cingulum and external capsule in at least nine animals per group under an 40ϫ objective using a 0.065-mm 2 -grid in three to four coronal sections for each animal at 48 h of recovery. Quantitative analysis of the optical density of MBPimmunoreactive fibers was done using image-analysis software (ImageJ, National Institutes of Health) as previously described (13). Nonspecific background density was measured at each brain level in an area devoid of MBP immunostaining and subtracted from the values for the cingulum.…”

“…Melatonin has demonstrated neuroprotective properties in adult models of cerebral ischemia, acting as a potent antioxidant and antiinflammatory agent (10,11). Melatonin was shown to have a potent protective effect in several models of developing white matter damage, by not only promoting oligodendroglial maturation and myelination repair but also decreasing astrogliosis and microglial activation (12)(13)(14)(15). We previously developed a neonatal model of stroke in 7-d-old (P7) rat characterized by apoptotic cell death (16,17), inflammatory responses (18,19), and oxidative stress (20).…”