ALTERATION OF MICRORNA EXPRESSION FOLLOWING TRAUMATIC SPINAL CORD INJURY: PATHOPHYSIOLOGY AT THE TRANSCRIPTOME LEVEL

Abstract

Spinal cord injury (SCI) imparts permanent neurological deficits and devastates many patients’ lives. The current management is not curative but focuses on blood pressure optimization, spinal cord (SC) decompression, spinal column stabilization, and rehabilitation. Despite progress in our understanding of the pathophysiological events that occur after the injury, there have been limitations in translating the success of preclinical animal studies into clinical scenarios. Therefore, a deeper understanding of SCI mechanisms is required. The initial impact on the SC results in parenchymal and vascular disruption (primary SCI). A few minutes after the primary SCI, a complex series of biochemical reactions (secondary injury) commence and may continue for several weeks and months. These reactions are regulated by specific sets of genes accompanied by changes in micro-Ribonucleic Acids (miRNAs) that inhibit and regulate gene translation. This thesis sought to understand SCI mechanisms from the perspective of changes to miRNA expression, subsequent impact on miRNA targets, and ultimately histological findings. For the first time, a neuroprotective drug was used to modulate the miRNA changes following the SCI. It was found that SCI results in extensive change in miRNA expression, primarily in the acute stage. Furthermore, administration of minocycline resulted in a further modulation of 81 miRNAs in the acute stage. The miRNAs most predicted to regulate genes participating in survival and apoptotic pathways were pursued. The miR-21a-5p and miR-15b-5p were upregulated by the injury and then downregulated following administration of minocycline. These two miRNAs target Akt, Bcl2, and PI3K genes, which are important for cell survival. An increased expression of these proteins was observed following downregulation of miR-21 and miR-15b. These findings were then correlated with enhanced neuronal survival in the injury penumbra. Modulation of miRNA expression by a neuroprotective agent may highlight the importance of miRNAs in this complex environment following SCI. Adopting such an approach may open novel pathways to potential SCI therapeutics to improve the SC healing process and eventually functional outcome.