Abstract
Spinal cord injury (SCI) causes neuronal cell death and vascular damage, which contribute to neurological dysfunction. Given that many biochemical changes contribute to such secondary injury, treatment approaches have increasingly focused on combined therapies or use of multi-functional drugs. MicroRNAs (miRs) are small (20–23 nucleotide), non-protein-coding RNAs and can negatively regulate target gene expression at the post-transcriptional level. As individual miRs can potentially modulate expression of multiple relevant proteins after injury, they are attractive candidates as upstream regulators of the secondary SCI progression. In the present study we examined the role of miR-711 modulation after SCI. Levels of miR-711 were increased in injured spinal cord early after SCI, accompanied by rapid downregulation of its target angiopoietin-1 (Ang-1), an endothelial growth factor. Changes of miR-711 were also associated with downregulation of the pro-survival protein Akt (protein kinase B), another target of miR-711, with sequential activation of glycogen synthase kinase 3 and the pro-apoptotic BH3-only molecule PUMA. Central administration of a miR-711 hairpin inhibitor after SCI limited decreases of Ang-1/Akt expression and attenuated apoptotic pathways. Such treatment also reduced neuronal/axonal damage, protected microvasculature and improved motor dysfunction following SCI. In vitro, miR-711 levels were rapidly elevated by neuronal insults, but not by activated microglia and astrocytes. Together, our data suggest that post-traumatic miR-711 elevation contributes to neuronal cell death after SCI, in part by inhibiting Ang-1 and Akt pathways, and may serve as a novel therapeutic target.
Highlights
Traumatic spinal cord injury (SCI) initiates a complex cascade of molecular events that leads to progressive degeneration
Results miR-711 is upregulated in the injured spinal cord tissue miRNA microarray profiling by GeneChip miRNA array revealed that central nervous system (CNS) trauma significantly upregulate the level of miR-711 in the ipsilateral cortex of controlled cortical impact mice[33] as well as the injured spinal cord
At 24 h after injection, western blot analysis demonstrated that SCI significantly decreased levels of Akt (p < 0.001, vs. Sham), general phosphorylated Akt and phosphorylated Akt (p < 0.01, vs. Sham, Fig. 2a, b), and markedly downregulated phosphorylation of Akt substrates GSK3α/ β (Fig. 2c, p < 0.001, vs. Sham)
Summary
Traumatic spinal cord injury (SCI) initiates a complex cascade of molecular events that leads to progressive degeneration These secondary injury processes include induction of multiple neuronal cell death pathways and vascular disruption, leading to neuronal loss, axonal. A number of miRNAs are enriched in neuronal cells and have important roles in central nervous system (CNS) development, function and pathologyincluding synaptic plasticity, dendritogenesis and structural remodeling[2]. Due to their ability to regulate entire networks of genes[3], neuronal miRs can act as “metacontrollers” of CNS gene expression[4,5]. It has been suggested that concurrent inhibition of multiple pro-apoptotic molecules, such as members of the BH3-only family of pro-apoptotic genes, may underlie the strong anti-apoptotic effects of certain miRs15–17
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
