MicroRNA Changes in Cerebrospinal Fluid After Subarachnoid Hemorrhage

Bache, Søren; Rasmussen, Rune; Rossing, Maria; Laigaard, Finn Pedersen; Nielsen, Finn Cilius; Møller, Kirsten

doi:10.1161/strokeaha.117.017804

Cited by 52 publications

(51 citation statements)

References 31 publications

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“…Previous studies demonstrated that miRNAs were involved in numerous physiological/pathological processes and were particularly appealing diagnostic and therapeutic tools for various diseases, including stroke, Parkinson's disease, traumatic brain injury (TBI), and Alzheimer's disease. Despite the fact that expression levels of miRNAs have measured in cerebrospinal fluid and in circulation, there are few studies investigating changes of miRNAs after SAH [12][13][14]. The blood-brain barrier (BBB) has been proven to be a major obstacle for delivery of drugs to the brain.…”

Section: Introductionmentioning

confidence: 99%

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

Lai

Liang

et al. 2020

J Neuroinflammation

138

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Background: Inflammation is a potential crucial factor in the pathogenesis of subarachnoid hemorrhage (SAH). Circulating microRNAs (miRNAs) are involved in the regulation of diverse aspects of neuronal dysfunction. The therapeutic potential of miRNAs has been demonstrated in several CNS disorders and is thought to involve modulation of neuroinflammation. Here, we found that peripherally injected modified exosomes (Exos) delivered miRNAs to the brains of mice with SAH and that the potential mechanism was regulated by regulation of neuroinflammation. Methods: Next-generation sequencing (NGS) and qRT-PCR were used to define the global miRNA profile of plasma exosomes in aSAH patients and healthy controls. We peripherally injected RVG/Exos/miR-193b-3p to achieve delivery of miR-193b-3p to the brain of mice with SAH. The effects of miR-193b-3p on SAH were assayed using a neurological score, brain water content, blood-brain barrier (BBB) injury, and Fluoro-Jade C (FJC) staining. Western blotting analysis, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR were used to measure various proteins and mRNA levels. Results: NGS and qRT-PCR revealed that four circulating exosomal miRNAs were differentially expressed. RVG/Exos exhibited improved targeting to the brains of SAH mice. MiR-193b-3p suppressed the expression and activity of HDAC3, upregulating the acetylation of NF-κB p65. Finally, miR-193b-3p treatment mitigated the neurological behavioral impairment, brain edema, BBB injury, and neurodegeneration induced by SAH, and reduced inflammatory cytokine expression in the brains of mice after SAH. Conclusions: Exos/miR-193b-3p treatment attenuated the inflammatory response by acetylation of the NF-κB p65 via suppressed expression and activity of HDAC3. These effects alleviated neurobehavioral impairments and neuroinflammation following SAH.

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Section: Introductionmentioning

confidence: 99%

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

Lai

Liang

et al. 2020

J Neuroinflammation

138

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“…Apoptosis and inflammation are tightly regulated processes at the level of gene expression. Profiling studies in humans have shown that miRNAs participate in different post-stroke pathologies and their levels are changed globally after SAH in CSF and circulation [16,18]. MiRNAs can represent tissue-specific molecular profiles that further define significant pathological features and individual miRNA may have a specific protective or pathogenic role.…”

Section: Discussionmentioning

confidence: 99%

“…They are known to participate in fundamental cellular processes such as cellular metabolism [13], cell-cycle regulation, including apoptosis [14] or immune response [15]. Several studies have indicated that specific miRNAs are involved in the regulation of inflammation and apoptosis after SAH and are clinically associated with the severity of brain injury [16][17][18]. However, no details are known about the early dynamics of miRNAs after SAH and about its association with the early dynamics of proinflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

TNFα and microRNA-15b expression changes in experimental model of subarachnoid haemorrhage

Ďuriš¹,

Lipková²,

Šplíchal³

et al. 2019

Cask Slov Neurol N

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Aim: The aim of the study was to investigate expression changes of pro-inflammatory and proapoptotic cytokine tumor necrosis factor alpha (TNFα) and microRNAs (miRNAs) involved in its regulation in early pathophysiological changes after subarachnoid haemorrhage (SAH). Materials and methods: MiRNAs (miR-125b, miR-146a, miR-346, miR-155, miR-15b) and mRNA (TNFα) expression were determined by quantitative real-time polymerase chain reaction in brain tissue samples. A total of 88 animals were divided to Sham (control surgery without induction of SAH), Mild SAH, Severe SAH groups in following time-points: 2, 4, 6 and 8 h (n = 7 per group); including 4 animals used as an absolute control. Results: We have found a statistically significant difference in TNFα expression between Sham and Severe SAH groups at all the time-points (p < 0.05), between Sham and Mild SAH groups 4 h after induction of SAH (p < 0.05) and between Mild and Severe SAH groups at 2 and 6 h time-points (p < 0.05). Furthermore, a significant difference in miR-15b expression between Sham and Severe SAH groups was observed 8 h after SAH (p < 0.05). All the other microRNAs have not been significantly changed. Conclusions: SAH was associated with an early increase in TNFα and miR-15b expression especially in Severe SAH group. Despite complex cross-regulation between cytokines and miRNA, any information about the activation of inflammation/ apoptotic mechanisms within a few hours after SAH may improve our knowledge of SAH pathophysiology. Furthermore, it can lead to therapeutic improvement using a combination of both pro-apoptotic markers TNFα and miR-15b. Souhrn Cíl: Cílem studie bylo prozkoumat změny v expresi pro-zánětlivého a pro-apoptotického cytokinu tumor nekrotizující faktor alfa (TNFα) a mikroRNA (miRNA), které se podílejí na jeho regulaci v časném období po subarachnoidálním krvácení (SAK). Soubor a metodika: Exprese miRNA (miR-125b, miR-146a, miR-346, miR-155, miR-15b) a mRNA (TNFα) byly stanoveny pomocí kvantitativní polymerázové řetězové reakce v reálném čase z mozkové tkáně experimentálních zvířat. Celkem 88 zvířat bylo rozděleno do skupin Sham (kontrolní operace bez indukce SAK), Lehké SAK, Těžké SAK, do časových intervalů 2, 4, 6 a 8 h (n = 7 ve skupině); 4 zvířata byla použita jako absolutní kontrola. Výsledky: Byly nalezeny statisticky významné rozdíly v expresi TNFα mezi skupinami Sham a Těžké SAK ve všech zkoumaných časových intervalech (p < 0,05), dále mezi skupinami Sham a Lehké SAK 4 h po indukci SAK (p < 0,05) a mezi skupinami Lehké SAK a Těžké SAK ve 2 a 6h časovém intervalu (p < 0,05). Dále byl pozorován významný rozdíl v expresi miRNA-15b mezi skupinami Sham a Těžké SAK 8 h po začátku SAK (p < 0,05). U dalších analyzovaných miRNA jsme v expresi nepozorovali žádné statisticky významné změny. Závěr: SAK bylo asociováno s časným nárůstem exprese TNFα a miR-15b, zejména u skupiny Těžké SAK. Navzdory komplexitě vzájemné regulace mezi cytokiny a mikroRNA, může informace o časné aktivaci zánětlivých/ apoptotických mechanismů několik hodin...

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“…All patients were treated with endovascular coiling. Neurologic outcome was assessed using the Modified Rankin Scale (mRS) at 1-year post-aSAH using a structured telephone interview [29] . If no contact was obtained after this procedure, the patient was declared lost to follow-up.…”

Section: Methodsmentioning

confidence: 99%

Increased interleukin-6 levels in neuron-derived plasma small extracellular vesicles in patients with aneurysmal subarachnoid hemorrhage

Lai

Yang

Qin

et al. 2020

Preprint

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Background Aneurysmal subarachnoid hemorrhage (aSAH) is a severe type of stroke characterized by high rates of mortality and disability. Identifying circulating biomarkers is helpful to improve prognosis. In this study, for the first time, we identify circulating interleukin-6 (IL-6) levels in neuronderived small extracellular vesicles (NDSEVs) as potential biomarkers in prognosis of aSAH.Methods We extracted small extracellular vesicles from the plasma of aSAH patients and healthy controls and enriched them using sequential precipitation and anti-L1CAM antibody immunoabsorption. Subsequently, we determined IL-6 levels using an enzyme-linked immunosorbent assay (ELISA).Results Plasma IL-6 NDSEVs showed distinct pattern differences between aSAH patients and healthy controls. There were significant correlations of IL-6concentrations in plasma with severity in aSAH.The AUCs of IL-6 for distinguishing the severe aSAH patients from mild aSAH patients were 0.961.After multivariate logistic regression analysis, only age, acute hydrocephalus,and the levels of IL-6NDSEVs enabled prediction of neurological outcome at 1 year. The IL-6 NDSEVs levels were greater and positively associated with disease and prognosis of aSAH patients.Conclusions These data suggest a neuroinflammatory cascade in aSAH patients. IL-6 NDSEVs may be a biomarkers to monitor the progression of aSAH.

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MicroRNA Changes in Cerebrospinal Fluid After Subarachnoid Hemorrhage

Abstract: Supplemental Digital Content is available in the text.

Cited by 52 publications

References 31 publications

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

TNFα and microRNA-15b expression changes in experimental model of subarachnoid haemorrhage

Increased interleukin-6 levels in neuron-derived plasma small extracellular vesicles in patients with aneurysmal subarachnoid hemorrhage

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