Abstract
Spinal cord injury (SCI) triggers a multitude of pathophysiological events that are tightly regulated by the expression levels of specific genes. Recent studies suggest that changes in gene expression following neural injury can result from the dysregulation of microRNAs, short non-coding RNA molecules that repress the translation of target mRNA. To understand the mechanisms underlying gene alterations following SCI, we analyzed the microRNA expression patterns at different time points following rat spinal cord injury.The microarray data reveal the induction of a specific microRNA expression pattern following moderate contusive SCI that is characterized by a marked increase in the number of down-regulated microRNAs, especially at 7 days after injury. MicroRNA downregulation is paralleled by mRNA upregulation, strongly suggesting that microRNAs regulate transcriptional changes following injury. Bioinformatic analyses indicate that changes in microRNA expression affect key processes in SCI physiopathology, including inflammation and apoptosis. MicroRNA expression changes appear to be influenced by an invasion of immune cells at the injury area and, more importantly, by changes in microRNA expression specific to spinal cord cells. Comparisons with previous data suggest that although microRNA expression patterns in the spinal cord are broadly similar among vertebrates, the results of studies assessing SCI are much less congruent and may depend on injury severity. The results of the present study demonstrate that moderate spinal cord injury induces an extended microRNA downregulation paralleled by an increase in mRNA expression that affects key processes in the pathophysiology of this injury.
Highlights
Traumatic spinal cord injury Spinal cord injury (SCI) is characterized by a specific pathophysiological response that can be divided into three phases
Processes occurring after SCI are associated with altered gene expression patterns; there is a strong upregulation of genes related to inflammation and cell death along with a downregulation of genes involved in cell excitability and neurotransmission within the first hours after injury
We observed that all groups presented homogeneous values, and the means of the BBB scores agreed with the moderate spinal cord injury values obtained in previous studies [7,9,11] (Figure 1A, B)
Summary
Traumatic spinal cord injury SCI is characterized by a specific pathophysiological response that can be divided into three phases. Processes occurring after SCI are associated with altered gene expression patterns; there is a strong upregulation of genes related to inflammation and cell death along with a downregulation of genes involved in cell excitability and neurotransmission within the first hours after injury. Upregulation of the genes involved in inflammation and apoptosis persist during the first weeks, whereas genes regulating cytoskeletal arrangement, myelin ensheathment and synapsis show decreased expression, reflecting compromised tissue integrity. Genes coding for angiogenic, neuritogenic and growth factors show increased expression, in an attempt to promote survival and regeneration [1]. This alteration of gene expression that is associated with processes triggered by SCI is thought to be accompanied by the post-transcriptional regulation of these modified gene networks. Preliminary studies using microarray analyses to examine microRNA expression profiles post-SCI in mice [5] and rats [6] have confirmed significant and common changes in the expression of several
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