Nicole Laferriere, MD, Wendy Kurata, MS, C. T. Grayson, MD, Lisa Pierce, DSc. Tripler Army Medical Center
OBJECTIVES: Gulf War Illness (GWI) is a chronic, multisymptom illness marked by cognitive and mood dysfunction and disrupted neuroendocrine-immune homeostasis affecting 30% of GW veterans. After 25+ years, useful treatments are lacking and its cause is poorly understood, although exposures to pyridostigmine bromide and pesticides are consistently identified among the strongest risk factors. Previous work in our laboratory using an established rat model of GWI identified persistent elevation of microRNA-124 (miR-124) levels in the hippocampus whose gene targets are involved in cognition-associated pathways and neuroendocrine function, suggesting that miR-124 inhibition is a promising therapeutic approach to improve the complex symptoms exhibited by GWI. The purpose of this study was to identify broad effects of miR-124 inhibition in the brain by profiling the expression of genes known to play a critical role in synaptic plasticity, glucocorticoid signaling, and neurogenesis in GWI rats administered a miR-124 antisense oligonucleotide (miR-124 inhibitor).
METHODS AND PROCEDURES: Nine months after completion of a 28-day exposure regimen involving GW-relevant chemicals and stress, rats underwent intracerebroventricular infusion of miR-124 inhibitor (n=9) or scrambled negative control oligonucleotide (n=8) and were implanted with 28-day osmotic pumps delivering 0.1 nmol/day. Intranasal delivery of oligonucleotides was performed on additional rats (n=4 per group; daily for 10 days) to determine whether miR-124 inhibition is achievable using a noninvasive procedure. Hippocampi were harvested and quantitative PCR arrays were used to profile the expression of focused panels of genes important for 1) synaptic alterations during learning and memory, 2) signaling initiated by the glucocorticoid receptor (known miR-124 target), and 3) neurogenesis. Hippocampi were also analyzed by quantitative PCR to examine expression levels of endogenous miR-124.
RESULTS: Upregulation (>2.5 fold change, p<0.05) of 8 synaptic plasticity genes, 11 glucocorticoid signaling genes, and 4 neurogenesis genes was observed in the hippocampus of GWI rats infused with miR-124 inhibitor compared to scrambled control, consistent with a significant reduction (p<0.001) in miR-124 levels detected in rats receiving miR-124 inhibitor. Altered gene expression and a reduction in miR-124 levels were not observed in rats after intranasal delivery.
CONCLUSION: miR-124 antagonism in the hippocampus upregulates the expression of several downstream targets involved in synaptic plasticity, glucocorticoid signaling, and neurogenesis and is a promising therapeutic approach to improve cognition, emotion regulation, and neuroendocrine dysfunction in GWI. Further testing is being pursued to discover the optimal dose for intranasal administration to test viability of this option for ill GW veterans.
Presented at the SAGES 2017 Annual Meeting in Houston, TX.
Abstract ID: 85995
Program Number: P077
Presentation Session: iPoster Session (Non CME)
Presentation Type: Poster