Inhibition of microRNA-124-3p as a novel therapeutic strategy for the treatment of Gulf War Illness: Evaluation in a rat model

• Published in: Neurotoxicology (Park Forest South) 2019-03, Vol.71, p.16-30
• Main Authors: Laferriere, Nicole R., Kurata, Wendy E., Grayson, Cary T., Stecklow, Kelsey M., Pierce, Lisa M.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antisense oligonucleotides; Brain; Central nervous system; Cognition; Cognition & reasoning; DEET; Disease Models, Animal; Drug delivery; Drug delivery systems; Exosomes; Exposure; Feasibility studies; Gene expression; Genes; Glucocorticoids; Glucocorticoids - metabolism; Gulf War; Gulf War Illness; Gulf War syndrome; Heart; Hippocampus; Hippocampus - metabolism; Illnesses; Immune system; In vivo methods and tests; Inhibition; Insecticides; Intracerebroventricular infusion; Male; microRNA-124-3p; MicroRNAs; MicroRNAs - antagonists & inhibitors; Military personnel; miRNA; Molecular modelling; Neuroendocrine system; Neurogenesis; Neuronal Plasticity; Next-generation sequencing; Oligonucleotides, Antisense - administration & dosage; Permethrin; Persian Gulf Syndrome - metabolism; Persian Gulf Syndrome - therapy; Persian Gulf War; Pesticides; Proteins; Pyridostigmine; Pyridostigmine bromide; Rats, Sprague-Dawley; Ribonucleic acid; Risk analysis; Risk factors; RNA; Rodents; Signaling; Signs and symptoms; Synaptic plasticity; Ventricle; Ventricles (cerebral); War
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2018.11.008

•Neurotoxic chemicals and stress caused persistent elevation in hippocampal miR-124-3p.•miR-124 inhibition increased synaptic plasticity and neuroendocrine gene expression.•Off-target cardiotoxic effects may occur at high doses of miR-124 inhibitor in brain.•Inhibition of miR-124 in the hippocampus is a promising therapeutic approach for GWI. Gulf War Illness (GWI) is a chronic, multisymptom illness that continues to affect up to 30% of veterans deployed to the Persian Gulf during the 1990–1991 Gulf War. After nearly 30 years, useful treatments for GWI are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood, although exposures to pyridostigmine bromide (PB) and pesticides are consistently identified to be among the strongest risk factors. Alleviation of the broad range of symptoms manifested in GWI, which involve the central nervous system, the neuroendocrine system, and the immune system likely requires therapies that are able to activate and inactivate a large set of orchestrated genes. Previous work in our laboratory using an established rat model of GWI identified persistent elevation of microRNA-124-3p (miR-124) levels in the hippocampus whose numerous gene targets are involved in cognition-associated pathways and neuroendocrine function. This study aimed to investigate the broad effects of miR-124 inhibition in the brain 9 months after completion of a 28-day exposure regimen of PB, DEET (N,N-diethyl-3-methylbenzamide), permethrin, and mild stress by profiling the hippocampal expression of genes known to play a critical role in synaptic plasticity, glucocorticoid signaling, and neurogenesis. We determined that intracerebroventricular infusion of a miR-124 antisense oligonucleotide (miR-124 inhibitor; 0.05-0.5 nmol/day/28 days), but not a negative control oligonucleotide, into the lateral ventricle of the brain caused increased protein expression of multiple validated miR-124 targets and increased expression of downstream target genes important for cognition and neuroendocrine signaling in the hippocampus. Off-target cardiotoxic effects were revealed in GWI rats receiving 0.1 nmol/day as indicated by the detection in plasma of 5 highly elevated protein cardiac injury markers and 6 upregulated cardiac-enriched miRNAs in plasma exosomes determined by next-generation sequencing. Results from this study suggest that in vivo inhibition of miR-124 function in the hippocampus is a promising, novel the