Basic ScienceSpatial and temporal expression levels of specific microRNAs in a spinal cord injury mouse model and their relationship to the duration of compression
Introduction
Spinal cord injury (SCI) affects approximately 12,000 individuals every year and causes devastating life-long disability as the result of poor neurologic recovery [1], [2]. The primary mechanical insult to the spinal cord initiates a deleterious cascade of events, leading to secondary injury including ischemia, edema, inflammation, and cellular necrosis [3], [4], [5], [6], which causes additional damage to neural elements by activating destructive pathophysiologic and pathobiochemical cascades [7], [8]. Compression is the most frequent mode of damage in traumatic SCI [9]. It has been shown that persistent compression of spinal cord causes potentially reversible processes of secondary injury [10], [11], [12]. Because the cellular and molecular mechanisms underlying secondary spinal cord injury are still not completely understood, the current treatments in the acute phase of compressive SCI are limited, with surgical decompression being the main stream of therapy. Although studies in animals have shown that early decompression, and as such shorter compression time, improves functional recovery, studies in humans have not been as successful [9], [10], [11]. Understanding the underlying molecular events that occur during prolonged compression is paramount in building new therapeutic strategies that can promote neurologic recovery [13], [14], [15], [16]. Several studies have demonstrated that duration of compression of spinal cord is directly correlated with significant physiological, histologic, and genetic alterations at a cellular level [8], [9], [14], [15]. After SCI, there is a down-regulation of genes related to synapses, cytoskeletal rearrangement, and neurotransmission, whereas genes involved in inflammation, ischemia, cell death, angiogenesis, and neurigenesis are up-regulated [15], [17].
MicroRNAs (miRNAs) are a class of small, nonprotein-coding RNA molecules [18], [19]. They modulate translation of specific genes, allowing them to fine-tune protein expression and thus regulate different physiologic and pathologic cellular processes [20], [21], [22], [23], [24], [25], [26]. Because the expression of many different gene products can be regulated by an individual miRNA, they are attractive candidates for effective interventions aimed to suppress pathophysiologic cellular responses to injury and environmental changes [27], [28]. It has been recently shown that miRNAs expression is altered in an SCI model [29], [30]. Furthermore, it has been shown that some miRNAs may play a role in the pathologic processes of secondary injury to the spinal cord [31], [32]. The majority of these studies have been performed on contusion models of SCI, which involve a single moment mechanical impact injury to the spinal cord. Hence, it is largely unknown whether the expression of miRNAs is altered with prolonged compression of the spinal cord. Furthermore, it is unknown whether miRNA expression is related to the duration of compression of spinal cord.
The goal of our study was to probe the relationship between the expression of six specific miRNAs and the timing of spinal cord decompression in a mouse model. Specifically we analyzed the changes in expression patterns of miR-29b, miR-30, miR-107, miR-148, miR-137, and miR-210 as related to the duration of spinal cord compression in an SCI mouse model. Furthermore we studied the expression changes of these specific miRNAs across two different spinal cord regions: at the injury level and rostral to the injury site.
Section snippets
SCI model
All work on animals was carried out at the animal facility of the University of Texas Health Science Center in San Antonio after being approved by the Animal Care and Use Committee at the UTHSCSA and complied with the National Institute of Health principles of laboratory animal care (NIH publication No. 80–23).
C57BL/6 male mice of 28 to 30 g of weight were used for these experiments. The surgical procedure was performed with animals under general anesthesia. Anesthesia was induced with a
Results
We evaluated expression patterns of six different miRNAs in a compressive spinal cord injury mouse model. It is known that the vascular injury plays an important role in SCI. Hence the majority of the miRNAs chosen for our study have been shown to change their expression levels in neuron and astrocytes placed in ischemic conditions [46]. To determine whether the length of compression influences the expression pattern of miRNAs we used two mouse models and compared the time-dependent expression
Discussion
The degree of neurologic disability after spinal cord trauma primarily depends on the extent of neural element loss and the remaining function of the residual neural tissue. Hence, it is important to reduce the loss of neurons induced by the secondary damage that occurs after the primary mechanical injury to the spine. Neurons and other cells in the central nervous system respond to injury by altering their gene and protein expression patterns and activating several molecular pathways that
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MicroRNA-31 regulating apoptosis by mediating the phosphatidylinositol-3 kinase/protein kinase B signaling pathway in treatment of spinal cord injury
2019, Brain and DevelopmentCitation Excerpt :In order to understand the relationship between miRNAs and SCI, the miRNAs expression changes were studied after SCI. With the advent of chip technology, most studies have shown that the level of miRNA changes in spinal cord tissues after SCI [54–57]. It has been reported that 269 miRNAs were found in normal spinal cord of rats, while 172 miRNAs remained unchanged.
MicroRNA-137 and its downstream target LSD1 inversely regulate anesthetics-induced neurotoxicity in dorsal root ganglion neurons
2017, Brain Research BulletinCitation Excerpt :We found out that miR-137-3p was significantly upregulated by Bv treatment in a dose-dependent manner. Similar pattern of miR-137 upregulation was also demonstrated in another spinal cord injury model, as physical compression caused miR-137 upregulation rostral to the compression site on mouse spinal cord (Ziu et al., 2014). These data suggest that, miR-137 may be dysregulated, possibly overexpressed in spinal cord neuronal populations in response to nerve injuries.
Synchrotron radiation micro-CT as a novel tool to evaluate the effect of agomir-210 in a rat spinal cord injury model
2017, Brain ResearchCitation Excerpt :As a named hypoxia-regulated miRNAs, miRNA-210 has been extensively studied, both in physiological and malignant conditions. In a recent publication, Ziu et al. identified miRNA-210 was up-regulated at 3, 6, and 24 h when the compression of spinal cord was sustained for ten minutes (Ziu et al., 2014b). In our contusion SCI model, miR-210 was down-regulated at day 1 post-SCI and remained at persistently low levels during the evaluation period in rat spinal cord following injury.
Micro RNA and its role in the pathophysiology of spinal cord injury - A further step towards neuroregenerative medicine
2015, Cirugia y Cirujanos (English Edition)Citation Excerpt :The remaining 37 micro RNAs expressed at a low level and were inhibited after the injury. As decompression of the spinal cord is the main surgical option, Ziu and co-authors19 carried out a study to analyse the spatial and temporary expression of the levels of different micro RNAs and their relationship with the duration of compression. These researchers managed to demonstrate that, depending on the compression time, the temporary expression of some micro RNAs is different.
Down regulation of lncSCIR1 after spinal cord contusion injury in rat
2015, Brain ResearchCitation Excerpt :These studies revealed changes in gene profiles at mRNA level. Recent studies extend such studies from coding mRNAs to post-transcriptional regulation and changes of non-coding RNA transcripts after CNS injury (Liu et al., 2008, 2012; Liu and Szaro, 2011; Liu et al., 2009; Ziu et al., 2014). For example, microRNA-486 (miR-486), miR-20a, and miR-21 are reported to be actively involved in the regulation of inflammation, cell death, and astrocyte reactivity respectively postSCI (Jee et al., 2012a, 2012b; Bhalala et al., 2012).
FDA device/drug status: Not applicable.
Author disclosures: MZ: Nothing to disclose. LF: Nothing to disclose. JGS: Nothing to disclose. DFJ: Nothing to disclose. MD: Nothing to disclose. VB: Nothing to disclose.
This work was supported in part by the University Research Council Grants Program at the University of Texas Health Science Center San Antonio (Grant 130267) and by the Department of Neurosurgery at the University of Texas Health Science Center at San Antonio, San Antonio, Texas. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.