Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy

Reschke, Cristina R.; Silva, Luiz Fernando Almeida; Norwood, Braxton A.; Senthilkumar, Ketharini; Morris, Gareth; Sanz-Rodríguez, Amaya; Conroy, Ronán; Costard, Lara S.; Neubert, Valentin; Bauer, Sebastian; Farrell, Michael; O’Brien, Donncha F.; Delanty, Norman; Schorge, Stephanie; Pasterkamp, R. Jeroen; Rosenow, Felix; Henshall, David C.

doi:10.1016/j.omtn.2016.11.002

Cited by 66 publications

(99 citation statements)

References 56 publications

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“…MiR-134 was found to be expressed in neurons in the brain and localized in dendrites. Increased miR-134 levels have been found in hippocampus of TLE patients and pentylenetetrazol-induced mice [30]. Previous work showed that silencing of miR-134 exhibited neuroprotective effects and reduces status epilepticus in vivo [16].…”

Section: Discussionmentioning

confidence: 99%

Antagomirs Targeting MicroRNA-134 Increase Limk1 Levels After Experimental Seizures in Vitro and in Vivo

Sun

Gao

Meng

et al. 2017

Cell Physiol Biochem

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Background: MiR-134 is enriched in dendrites of hippocampal neurons and plays crucial roles in the progress of epilepsy. The present study aims to investigate the effects of antagomirs targeting miroRNA-134 (Ant-134) on limk1 expression and the binding of miR-134 and limk1 in experimental seizure. Methods: Status epilepticus (SE) rat model was established by lithium chloride-pilocarpine injection and was treated with Ant-134 by intracerebroventricular injection. Low Mg²⁺-exposed primary neurons were used as an in vitro model of SE. The expression of miR-134 was determined using real-time PCR. Protein expressions of limk1 and cofilin were determined by Western blotting. Luciferase reporter assay was used to examine the binding between miR-134 and limk1 3’-untranslated region. Results: The expression of miR-134 was markedly enhanced in hippocampus of the SE rats and low Mg²⁺-exposed neurons. Ant-134 increased the expression of limk1 and reduced the expression of cofilin in the SE hippocampus and Low Mg²⁺-exposed neurons. In addition, luciferase reporter assay confirmed that miR-134 bound limk1 3’-UTR. MiR-134 overexpression inhibited limk1 mRNA and protein expressions in neurons. Conclusion: Blockage of miR-134 upregulates limk1 expression and downregulated cofilin expression in hippocampus of the SE rats. This mechanism may contribute to the neuroprotective effects of Ant-134.

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Section: Discussionmentioning

confidence: 99%

Antagomirs Targeting MicroRNA-134 Increase Limk1 Levels After Experimental Seizures in Vitro and in Vivo

Sun

Gao

Meng

et al. 2017

Cell Physiol Biochem

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“…Similarly to the in vivo study, they showed increased miR‐134 levels after seizure‐like electrographic activity, and lentiviral miR‐134 inhibition reduced neuronal hyperactivity and neuronal cell death (Wang et al, ). Most recently, the potential and relevance of miR‐134 antagomirs as antiepileptic drugs was further corroborated in a study combining the analysis of human tissue with three additional rodent epilepsy models (Reschke et al, ). This study confirmed that miR‐134 was significantly up‐regulated in hippocampal tissue from patients with refractory TLE.…”

Section: Candidate Micrornas With Therapeutic Potential In Epilepsy Amentioning

confidence: 90%

“…Moreover, miR‐134 was shown to control neuronal development by targeting the neuronal migration proteins Doublecortin (DCX) and Chordin‐like 1 (Chrdl1) (Gaughwin et al, ), and synaptic homoeostasis by controlling the RNA‐binding protein Pumilio‐2 (Pum2) (Fiore et al, ). As a first indication of miR‐134's role in epilepsy, two articles in 2011 reported that miR‐134 is up‐regulated after kainic acid‐induced seizures in mice and in a rat model of pilocarpine‐induced TLE (Jimenez‐Mateos et al, ; Song et al, ), which was confirmed in later studies in additional rodent seizure models as well as in human intractable TLE (Jimenez‐Mateos et al, , ; Peng et al, ; Reschke et al, ). Using an intra‐amygdala kainic acid model of epilepsy, Jimenez‐Mateos et al () were the first to investigate the functional role of a microRNA in seizure susceptibility (Jimenez‐Mateos et al, ).…”

Section: Candidate Micrornas With Therapeutic Potential In Epilepsy Amentioning

confidence: 91%

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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“…30 Thus, microRNAs exert biologically meaningful control over expression of ion channels that regulate brain excitability. 33 Treating rats with antisense molecules targeting miR-134 after triggering electrical status epilepticus reduced by 86% the later development of epilepsy. To date, inhibiting miR-134 has been shown to reduce or delay status epilepticus in the intra-amygdala kainate 31 and systemic pilocarpine models.…”

Section: Noncoding Rnasmentioning

confidence: 99%

“…There has been further progress on the therapeutic potential of targeting miR-134 in seizure models. 33 Questions turn now to preclinical development, where factors such as delivery to the site of pathology must be considered. 32 In recent work, we showed that reducing miR-134 levels also delayed tonic-clonic convulsions induced by pentylenetetrazol in mice.…”

Section: Noncoding Rnasmentioning

confidence: 99%

Epigenetic changes in status epilepticus

Henshall

2018

Epilepsia

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Epigenetics refers broadly to processes that influence medium- to long-term expression of genes through changes to the readability and accessibility of the genome to transcription. The mediators include DNA methylation, posttranslational modification of histone proteins, and noncoding RNAs. The present review focuses on recent findings showing epigenetic processes influence susceptibility to and severity of status epilepticus, while status epilepticus in turn drives changes to epigenetic marks that affect the gene expression landscape underlying epileptogenesis. Experimental status epilepticus triggers select, spatiotemporal hypo- and hypermethylation changes throughout the genome. Experimental manipulations that alter DNA methylation after status epilepticus are associated with amelioration of cognitive and hyperexcitability phenotypes. Prolonged seizures also modify chromatin compaction via acetylation and other changes to histones and their expression. Finally, short noncoding RNAs called microRNAs target networks of genes through posttranscriptional and other mechanisms and their modulation can alter status epilepticus as well as serve as potential molecular biomarkers. Long noncoding RNAs have also been targeted to influence expression of genes affecting electrophysiological functions of neurons. In summary, epigenetic processes can modulate status epilepticus, and status epilepticus imposes changes on the epigenome, which together provide novel insight into pathomechanisms, therapy, and biomarkers for status epilepticus.

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Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy

Cited by 66 publications

References 56 publications

Antagomirs Targeting MicroRNA-134 Increase Limk1 Levels After Experimental Seizures in Vitro and in Vivo

Antagomirs Targeting MicroRNA-134 Increase Limk1 Levels After Experimental Seizures in Vitro and in Vivo

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

Epigenetic changes in status epilepticus

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