hsa-MiR-19a-3p and hsa-MiR-19b-3p Are Associated with Spinal Cord Injury-Induced Neuropathic Pain: Findings from a Genome-Wide MicroRNA Expression Profiling Screen

Abstract

Neuropathic pain in spinal cord injury (SCI) is associated with inflammation in both the peripheral and central nervous system (CNS), which may contribute to the initiation and maintenance of persistent pain. An understanding of factors contributing to neuroinflammation may lead to new therapeutic targets for neuropathic pain. Moreover, novel circulating biomarkers of neuropathic pain may facilitate earlier and more effective treatment. MicroRNAs (miRNAs) are short, non-coding single-stranded RNA that have emerged as important biomarkers and molecular mediators in physiological and pathological conditions. Using a genome-wide miRNA screening approach, we studied differential miRNA expression in plasma from 68 healthy, community-dwelling adults with and without SCI enrolled in ongoing clinical studies. We detected 2367 distinct miRNAs. Of these, 383 miRNAs were differentially expressed in acute SCI or chronic SCI versus no SCI and 71 were differentially expressed in chronic neuropathic pain versus no neuropathic pain. We selected homo sapiens (hsa)-miR-19a-3p and hsa-miR-19b-3p for additional analysis based on p -value, fold change, and their known role as regulators of neuropathic pain and neuroinflammation. Both hsa-miR-19a-3p and hsa-miR-19b-3p levels were significantly higher in those with chronic SCI and severe neuropathic pain versus those with chronic SCI and no neuropathic pain. In confirmatory studies, both hsa-miR-19a-3p and hsa-miR-19b-3p have moderate to strong discriminative ability to distinguish between those with and without pain. After adjusting for opioid use, hsa-miR-19b-3p levels were positively associated with pain interference with mood. Because hsa-miR-19 levels have been shown to change in response to exercise, folic acid, and resveratrol, these studies suggest that miRNAs are potential targets of therapeutic interventions.

Exosomal MicroRNAs modulate the cognitive function in fasudil treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer's disease

“…3.1 mmu-miR-19a-3p miRNA alterations in CNS and PNS in uence microglial activity and neuroin ammation by orchestrating the expression of proteins, which controls activation or inhibition of microglial activity. A recent clinical study reports that hsa-miR-19a-3p and hsa-miR-19b-3p expression distinctly discriminative the pain severity in spinal cord injury-induced neuropathic pain 32 . Increased expression of miR-19a-3p in the exosomes of α-synuclein gene transgenic SH-SY5Y cells has been reported, while enhanced expression of miR-19a-3p in exosomes suppresses autophagy in recipient microglia by targeting the phosphatase and tensin homolog/AKT/mTOR signaling pathway 33 .…”

“…Akt3 is also required for the nuclear export receptor, CRM-1 52 . MiR-485-3p serves as a biomarker and therapeutic target of AD via regulating neuronal cell viability and neuroin ammation by targeting Akt3 32 .…”

MiRNAs as Promising Translational Strategies for Neuronal Repair and Regeneration in Spinal Cord Injury

“…MiR19a-targeted Methyl-CpG Binding Protein 2 (MeCP2), Ras homolog family member B (RhoB), suppressor of cytokine signaling 1 (SOCS1), Leucine-rich repeats and Immunoglobulin-like domains 1 (LRIG1), and Peroxisome Proliferator-Activated Receptor Alpha (PPARα); while the miR-19b targeted signal transduction and activator of transcription 3 (STAT3) and FMR1 Autosomal Homolog 1 (FXR1). Neuropathic pain occurs at or below the lesion level, and it is refractory to most treatments, thus the identification of biomarkers could be useful in identifying new pharmacological and non-pharmacological strategies [ 97 ].…”

MicroRNA-148a-3p is a candidate mediator of increased bone marrow adiposity and bone loss following spinal cord injury

“…From this trial, participants were excluded if they were enrolled in another clinical trial or had contraindications to simvastatin. Additional exclusion criteria can be found in (17) and included metabolic bone disease, untreated thyroid disease, history of bilateral oophorectomy, active use of medications potentially affecting bone health (bisphosphonates, androgenic steroids, estrogenic steroids, anti-epileptics and lithium, glucocorticoids), and those who received inhaled glucocorticoids in the past year, pregnant or lactating women and women of childbearing potential who were unwilling or unable to use a reliable form of contraception.…”

“…Samples were then: 1) centrifuged for 15 min at 2600 rpm (1459 x g) at 40C and 2) stored at -80 0 C until analysis. All microRNA analyses were performed by LC Sciences at their facilities in Houston, TX, as previously described (17,20). Briefly, a comprehensive miRNA/small RNA sequencing service was performed, which included: sample QC, library preparation, and sequencing (50 base pair sequencing, on average a minimum of 7-10 million reads per sample).…”