Different MicroRNA Profiles in Chronic Epilepsy Versus Acute Seizure Mouse Models

Kretschmann, Anita; Danis, Bénédicte; Andonovic, Lidija; Abnaof, Khalid; Rikxoort, Marijke van; Siegel, Franziska; Mazzuferi, Manuela; Godard, Patrice; Hanon, Étienne; Fröhlich, Holger; Kamiński, Rafał M.; Foerch, Patrik; Pfeifer, Alexander

doi:10.1007/s12031-014-0368-6

Cited by 61 publications

(66 citation statements)

References 75 publications

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“…We did not observe an increase in miR-134 after perforant pathway stimulation in the rat. This was surprising, although changes to miR-134 levels are not always detected after chemoconvulsive stimuli, 37 and we cannot rule out a technical explanation (e.g., the time points selected or a subfield-specific effect that was masked by the use of the whole hippocampus).…”

Section: Discussionmentioning

confidence: 82%

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

Reschke

Silva

Norwood

et al. 2017

Molecular Therapy - Nucleic Acids

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Current anti-epileptic drugs (AEDs) act on a limited set of neuronal targets, are ineffective in a third of patients with epilepsy, and do not show disease-modifying properties. MicroRNAs are small noncoding RNAs that regulate levels of proteins by post-transcriptional control of mRNA stability and translation. MicroRNA-134 is involved in controlling neuronal microstructure and brain excitability and previous studies showed that intracerebroventricular injections of locked nucleic acid (LNA), cholesterol-tagged antagomirs targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in mouse models of status epilepticus. Translation of these findings would benefit from evidence of efficacy in non-status epilepticus models and validation in another species. Here, we report that electrographic seizures and convulsive behavior are strongly reduced in adult mice pre-treated with Ant-134 in the pentylenetetrazol model. Pre-treatment with Ant-134 did not affect the severity of status epilepticus induced by perforant pathway stimulation in adult rats, a toxin-free model of acquired epilepsy. Nevertheless, Ant-134 post-treatment reduced the number of rats developing spontaneous seizures by 86% in the perforant pathway stimulation model and Ant-134 delayed epileptiform activity in a rat ex vivo hippocampal slice model. The potent anticonvulsant effects of Ant-134 in multiple models may encourage pre-clinical development of this approach to epilepsy therapy.

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Section: Discussionmentioning

confidence: 82%

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

Reschke

Silva

Norwood

et al. 2017

Molecular Therapy - Nucleic Acids

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“…3A ). A previous study identified miR-324-5p as one of several microRNAs that were downregulated in the hippocampus 24 hours following pilocarpine-induced status epilepticus (Kretschmann et al, 2015), but this result was not reproduced in a similar study using kainic acid to induce seizures (Jimenez-Mateos et al, 2011). Another study showed hippocampal upregulation of miR-324-5p in a rat epilepsy model 60 days following lithium-pilocarpine-induced status epilepticus (Song et al, 2011).…”

Section: Discussionmentioning

confidence: 90%

MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset

et al. 2016

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Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4.2 protein. We show that the microRNA miR-324-5p inhibits Kv4.2 protein expression and that antagonizing miR-324-5p is neuroprotective and seizure-suppressive. MiR-324-5p inhibition also blocks kainic acid-induced reduction of Kv4.2 protein in vitro and in vivo and delays kainic acid-induced seizure onset in wild type but not in Kcnd2 knockout mice. These results reveal an important role for miR-324-5p-mediated silencing of Kv4.2 in seizure onset.

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“…Previous studies suggested that the miRNA profile is altered during epilepsy, 5,6 including the expression of miR-199a-5p. 7,8 miR-199a was also shown to be expressed specifically in neural tissues, such as the hippocampus, 9 and to be associated with neuronal process outgrowth, regeneration, and synaptic plasticity in damaged neurons through targeting mammalian target of rapamycin (mTOR). 10 In addition, miR-199a has been associated with apoptosis in many diseases.…”

mentioning

confidence: 99%

Targeting of microRNA‐199a‐5p protects against pilocarpine‐induced status epilepticus and seizure damage via SIRT1‐p53 cascade

Wang

Zhang

et al. 2016

Epilepsia

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SUMMARYObjective: MicroRNAs (miRNAs) are noncoding small RNAs that control gene expression at the posttranscriptional level. Some dysregulated miRNAs have been shown to play important roles in epileptogenesis. The aim of this study was to determine if miR199a-5p regulates seizures and seizure damage by targeting the antiapoptotic protein silent information regulator 1 (SIRT1). Methods: Hippocampal expression levels of miR-199a-5p, SIRT1, and acetylated p53 were quantified by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting in the acute, latent, and chronic stages of epilepsy in a rat lithiumpilocarpine epilepsy model. Silencing of miR-199a-5p expression in vivo was achieved by intracerebroventricular injection of antagomirs. The effects of targeting miR-199a-5p and SIRT1 protein on seizure and epileptic damage post-status epilepticus were assessed by electroencephalography (EEG) and immunohistochemistry, respectively. Results: miR-199a-5p expression was up-regulated, SIRT1 levels were decreased, and neuron loss and apoptosis were induced in epilepsy model rats compared with normal controls, as determined by up-regulation of acetylated p53 and cleaved caspase-3 expression. In vivo knockdown of miR-199a-5p by an antagomir alleviated the seizurelike EEG findings and protected against neuron damage, in accordance with up-regulation of SIRT1 and subsequent deacetylation of p53. Furthermore, the seizure-suppressing effect of the antagomir was partly SIRT1 dependent. Significance: The results of this study suggest that silencing of miR-199a-5p exerts a seizure-suppressing effect in rats, and that SIRT1 is a direct target of miR-199a-5p in the hippocampus. The effect of miR-199a-5p on seizures and seizure damage is mediated via down-regulation of SIRT1. The miR-199a-5p/SIRT1 pathway may thus represent a potential target for the prevention and treatment of epilepsy and epileptic damage.

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Different MicroRNA Profiles in Chronic Epilepsy Versus Acute Seizure Mouse Models

Cited by 61 publications

References 75 publications

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

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

MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset

Targeting of microRNA‐199a‐5p protects against pilocarpine‐induced status epilepticus and seizure damage via SIRT1‐p53 cascade

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