Abstract
Axonal regeneration after spinal cord injury (SCI) is difficult to achieve, and no fundamental treatment can be applied in clinical settings. DNA methylation has been suggested to play a role in regeneration capacity and neuronal growth after SCI by controlling the expression of regeneration-associated genes (RAGs). The aim of this study was to examine changes in neuronal DNA methylation status after SCI and to determine whether modulation of DNA methylation with ascorbic acid can enhance neuronal regeneration or functional restoration after SCI. Changes in epigenetic marks (5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC)); the expression of Ten-eleven translocation (Tet) family genes; and the expression of genes related to inflammation, regeneration, and degeneration in the brain motor cortex were determined following SCI. The 5hmC level within the brain was increased after SCI, especially in the acute and subacute stages, and the mRNA levels of Tet gene family members (Tet1, Tet2, and Tet3) were also increased. Administration of ascorbic acid (100 mg/kg) to SCI rats enhanced 5hmC levels; increased the expression of the Tet1, Tet2, and Tet3 genes within the brain motor cortex; promoted axonal sprouting within the lesion cavity of the spinal cord; and enhanced recovery of locomotor function until 12 weeks. In conclusion, we found that epigenetic status in the brain motor cortex is changed after SCI and that epigenetic modulation using ascorbic acid may contribute to functional recovery after SCI.
Highlights
Axonal regeneration following spinal cord injury (SCI) is difficult to achieve, and no fundamental treatment can be applied in clinical settings
Macrophage infiltration into the lesion site was detected by immunohistological staining (Figure 1B), and we found that ED1 + cells were most visible in the lesion cavity 1 week after SCI, and gradually decreased after 1 and 3 months (Figure 1C)
We found that most Tet1-positive cells at 1 week after injury were NeuN-positive neurons (88.6 ± 2.9%), and relatively few cells were observed in adenomatous polyposis coli (APC)-positive oligodendrocytes (13.4 ± 6.1%) and glial fibrillary acidic protein (GFAP)-positive astrocytes (6.4 ± 4.2%)
Summary
Axonal regeneration following spinal cord injury (SCI) is difficult to achieve, and no fundamental treatment can be applied in clinical settings. Epigenetic regulation mechanisms are important for the development of the central nervous system (CNS), and interactions with environmental factors can change gene expression [1]. Epigenetic changes may play roles in the regeneration capacity of damaged neurons in the adult brain, as well as in neuronal growth in the developing brain; the supraspinal mechanism of epigenetic changes after SCI is still elusive. 5-position of the cytosine base (5mC) plays critical roles in modulating gene expression, and in regulating cellular and developmental processes [2]. TET dioxygenases depend on ferrous iron and 2-oxoglutarate (2OG), and are members of a large family of enzymes that catalyze a wide range of oxidative reactions; these enzymes are catalysts for epigenetic modifications of DNA and histones [2]
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