Modulation of <i>miR-146a</i>/complement factor H-mediated inflammatory responses in a rat model of temporal lobe epilepsy

He, Fang; Liu, Bei; Meng, Qingwei; Sun, Yang; Wang, Weiwen; Wang, Chao

doi:10.1042/bsr20160290

Cited by 36 publications

(48 citation statements)

References 63 publications

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“…On the other hand, a pro-inflammatory profile has also been reported. He et al demonstrated that miR-146a inhibition decreased seizure susceptibility in animal models [25]. It is yet to be completely understood if miR-146a acts as neuroprotective/antiinflammatory or neurodamaging/pro-inflammatory factor in epilepsy.…”

Section: Discussionmentioning

confidence: 99%

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Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panel

Martins-Ferreira

Chaves

Carvalho

et al. 2019

Euro J of Neurology

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Background and purpose Genetic generalized epilepsies (GGEs) encompass a group of syndromes of mainly genetic causes, characterized by the involvement of both hemispheres. MicroRNAs (miRNAs) are small non‐coding RNAs with a critical role in the regulation of neuronal biological processes through gene expression modulation. Dysregulated miRNA expression has been shown in epilepsy. Due to their stability in biological fluids like serum, miRNAs have assumed a prominent role in biomarker research. Our aim was to evaluate circulating levels of three miRNAs in GGE patients and assess their putative diagnostic value. Methods MiR‐146a, miR‐155 and miR‐132 were quantified by real‐time polymerase chain reaction in the serum of 79 GGE patients (47 women, 32 men, 35.1 ± 12.4 years) and 67 healthy individuals (41 women, 26 men, 42.4 ± 10.1 years). Relative expression values were calculated using the 2–ΔΔCt method. Receiver operating characteristic curve analysis was performed to assess diagnostic value. MiRNA expression was correlated with clinicopathological features. Results Serum levels of miR‐146a and miR‐155 were significantly upregulated in GGE patients relative to controls (3.13 and 6.05, respectively). Combined miR‐146a, miR‐155 and miR‐132 serum levels performed well as a diagnostic biomarker, discriminating GGE patients from controls with an area under the curve of 0.85, 80% specificity and 73% sensitivity. Conclusions Our results indicate that miR‐146a, miR‐155 and miR‐132 may partake in GGE epileptogenesis. A panel of three circulating miRNAs with potential value as a GGE biomarker is reported for the first time. Novel biomarkers may help to identify new treatment targets and contribute to improved patients’ quality of life through earlier diagnosis and a more precise prognosis.

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Section: Discussionmentioning

confidence: 99%

“…Recently, a new wave of biomarker research has emerged, focusing on epigenetic markers, with micro-RNAs (miRNAs) assuming a prominent role. MiR-NAs are small non-coding RNA molecules (19)(20)(21)(22)(23)(24)(25) nucleotides in length) that function as post-transcriptional regulators of gene expression [8].…”

Section: Introductionmentioning

confidence: 99%

Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panel

Martins-Ferreira

Chaves

Carvalho

et al. 2019

Euro J of Neurology

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“…The enduring seizure‐suppressing effect of transient miR‐146a supplementation in early stages of epilepsy suggests an epileptogenesis‐inhibiting and thus disease‐modulating effect of miR‐146a. In contrast, He et al reported that the opposite strategy, i.e., miR‐146a inhibition with a single intracerebroventricular injection of a miR‐146a antagomir, reduced seizure frequency in a rat model of TLE (He et al, ). This apparent controversy, which may be due to different timing, different epilepsy models or potential off‐target effects, requires further detailed analysis of the function of this microRNA in seizure regulation and epileptogenesis.…”

Section: Candidate Micrornas With Therapeutic Potential In Epilepsy Amentioning

confidence: 98%

“…MiR‐146a is of particular interest for epilepsy etiology because it is highly expressed in astrocytes and regulates neuroinflammation (Li et al, ; Iyer et al, ; Kong et al, ), a process believed to be involved in epileptogenesis (Vezzani et al, ). Indeed, miR‐146a expression was shown to be the highest during epileptogenesis, i.e., in the latent and chronic stages in rat models of TLE (Aronica et al, ; Hu et al, ; Omran et al, ; He et al, ). Omran et al () also found up‐regulated levels of miR‐146a in children with mesial TLE (mTLE) confirming earlier work in human TLE (Aronica et al, ).…”

Section: Candidate Micrornas With Therapeutic Potential In Epilepsy Amentioning

confidence: 99%

“…While the majority of studies suggest miR‐146a has significant anti‐inflammatory properties that attenuate but do not abrogate acute and recurrent seizures in animal models of TLE, there may be other pro‐inflammatory mechanisms of miR‐146a that could promote development of spontaneous recurrent seizures. Work by He et al suggests that complement factor H (CFH), a crucial suppressor of the innate immune system through inhibiting the transition of complement factor C3 to C3b, is a target of miR‐146a, and CFH is down‐regulated in a rat model of TLE where miR‐146a is induced (He et al, ). Lack of complement inhibition can lead to a state of chronic inflammation, not uncommonly found in brains from patients with refractory epilepsy (Vezzani and Viviani, ).…”

Section: Micrornas Regulating Inflammation In Epilepsy and Epileptogementioning

confidence: 99%

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MicroRNA‐induced silencing in epilepsy: Opportunities and challenges for clinical application

Tiwari

Peariso

Groß

2017

Developmental Dynamics

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MicroRNAs are master regulators of gene expression. Single microRNAs influence multiple proteins within diverse molecular pathways and networks. Therefore, changes in levels or activity of microRNAs can have profound effects on cellular function. This makes dysregulated microRNA-induced silencing an attractive potential disease mechanism in complex disorders like epilepsy, where numerous cellular pathways and processes are affected simultaneously. Indeed, several years of research in rodent models have provided strong evidence that acute or recurrent seizures change microRNA expression and function. Moreover, altered microRNA expression has been observed in brain and blood from patients with various epilepsy disorders, such as tuberous sclerosis. MicroRNAs can be easily manipulated using sense or antisense oligonucleotides, opening up opportunities for therapeutic intervention. Here, we summarize studies using these techniques to identify microRNAs that modulate seizure susceptibility, describe protein targets mediating some of these effects, and discuss cellular pathways, for example neuroinflammation, that are controlled by epilepsy-associated microRNAs. We critically assess current gaps in knowledge regarding target-and cell-specificity of microRNAs that have to be addressed before clinical application as therapeutic targets or biomarkers. The recent progress in understanding microRNA function in epilepsy has generated strong momentum to encourage in-depth mechanistic studies to develop microRNA-targeted therapies. Developmental Dynamics 247:94-110, 2018. V C 2017 Wiley Periodicals, Inc.

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Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy

et al. 2021

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Objective: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice results in handling-induced seizures and is useful for evaluating compounds effective against infection-induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has not yet been performed. Furthermore, as the TMEV infection produces marked neuroinflammation, an evaluation of prototype anti-inflammatory compounds is needed as well.Methods: Male C57Bl/6J mice were inoculated with TMEV (day 0) followed by daily administrations of test compounds (day 3-7) and subsequent handling sessions (day 3-7). Doses of ASMs, comprising several mechanistic classes, were selected based on previously published data demonstrating the effect of these compounds in reducing seizures in the 6 Hz model of pharmacoresistant seizures. Doses of anti-inflammatory compounds, comprising several mechanistic classes, were selected based on published evidence of reduction of inflammation or inflammation-related endpoints.Results: Several prototype ASMs reduced acute seizures following TMEV infection: lacosamide, phenytoin, ezogabine, phenobarbital, tiagabine, gabapentin, levetiracetam, topiramate, and sodium valproate. Of these, phenobarbital and sodium valproate had the greatest effect (>95% seizure burden reduction).Prototype anti-inflammatory drugs celecoxib, dexamethasone, and prednisone also moderately reduced seizure burden.

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Modulation of miR-146a/complement factor H-mediated inflammatory responses in a rat model of temporal lobe epilepsy

Cited by 36 publications

References 63 publications

Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panel

Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panel

MicroRNA‐induced silencing in epilepsy: Opportunities and challenges for clinical application

Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy

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