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 therapeutic approach to improve cognition and neuroendocrine dysfunction in GWI. Additional preclinical studies in animal models to assess feasibility and safety by developing a practical, noninvasive drug delivery system to the brain and exploring potential adverse toxicologic effects of miR-124 inhibition are warranted.

中文翻译：

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抑制microRNA-124-3p作为治疗海湾战争疾病的新型治疗策略：在大鼠模型中进行评估。

海湾战争疾病（GWI）是一种慢性多症状疾病，在1990-1991年海湾战争期间，这种疾病继续影响着部署到波斯湾的退伍军人中的30％。经过将近30年的研究，缺乏对GWI的有效治疗方法，并且尽管人们始终认为暴露于溴化吡啶斯的明溴化物（PB）和杀虫剂是最强的危险因素，但其病理生物学中涉及的基本细胞和分子机制仍知之甚少。减轻GWI表现出的广泛症状，涉及中枢神经系统，神经内分泌系统和免疫系统，可能需要能够激活和灭活大量精心策划的基因的疗法。在我们实验室中，使用已建立的GWI大鼠模型的先前工作确定了海马中microRNA-124-3p（miR-124）水平的持续升高，其许多基因靶标与认知相关的途径和神经内分泌功能有关。这项研究的目的是通过分析28天的PB，DEET（N，N-二乙基-3-甲基苯甲酰胺），苄氯菊酯和轻度应激的28天暴露方案完成后9个月，研究miR-124抑制对大脑的广泛影响。已知在突触可塑性，糖皮质激素信号传导和神经发生中起关键作用的基因的海马表达。我们确定脑室内注入了miR-124反义寡核苷酸（miR-124抑制剂； 0.05-0.5 nmol /天/ 28天），但没有阴性对照寡核苷酸，进入大脑侧脑室会导致多个经过验证的miR-124靶标的蛋白表达增加，并且对海马体的认知和神经内分泌信号转导很重要的下游靶标基因的表达也增加。血浆中检测到5种高度升高的蛋白心脏损伤标记物和6种上调的心脏富集的miRNA，通过下一代测序确定，在接受0.1 nmol /天的GWI大鼠中显示出脱靶的心脏毒性作用。这项研究的结果表明，体内抑制海马中的miR-124功能是一种有前途的新颖治疗方法，可改善GWI中的认知和神经内分泌功能障碍。通过开发实用的，