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

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Abstract

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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Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.

Lee P. Lim, Nelson C. Lau, Philip Garrett-Engele … (2005)

MicroRNAs (miRNAs) are a class of noncoding RNAs that post-transcriptionally regulate gene expression in plants and animals. To investigate the influence of miRNAs on transcript levels, we transfected miRNAs into human cells and used microarrays to examine changes in the messenger RNA profile. Here we show that delivering miR-124 causes the expression profile to shift towards that of brain, the organ in which miR-124 is preferentially expressed, whereas delivering miR-1 shifts the profile towards that of muscle, where miR-1 is preferentially expressed. In each case, about 100 messages were downregulated after 12 h. The 3' untranslated regions of these messages had a significant propensity to pair to the 5' region of the miRNA, as expected if many of these messages are the direct targets of the miRNAs. Our results suggest that metazoan miRNAs can reduce the levels of many of their target transcripts, not just the amount of protein deriving from these transcripts. Moreover, miR-1 and miR-124, and presumably other tissue-specific miRNAs, seem to downregulate a far greater number of targets than previously appreciated, thereby helping to define tissue-specific gene expression in humans.

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A brain-specific microRNA regulates dendritic spine development.

Gerhard M Schratt, Fabian Tuebing, Elizabeth Nigh … (2006)

MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.

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Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

Alexandre Carpentier, Michael Canney, Alexandre Vignot … (2016)

The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.

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Author and article information

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David C. Henshall

Journal

Journal ID (nlm-ta): Mol Ther Nucleic Acids

Journal ID (iso-abbrev): Mol Ther Nucleic Acids

Title: Molecular Therapy. Nucleic Acids

Publisher: American Society of Gene & Cell Therapy

ISSN (Electronic): 2162-2531

Publication date PMC-release: 10 December 2016

Publication date (Print): 17 March 2017

Publication date (Electronic): 10 December 2016

Volume: 6

Pages: 45-56

Affiliations

[1 ]Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland

[2 ]Department of Neurology, Philipps University, Marburg 35043, Germany

[3 ]Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany

[4 ]Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands

[5 ]Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, London WC1N 3BG, UK

[6 ]Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland

[7 ]Department of Pathology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland

[8 ]Department of Neurological Surgery, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland

[9 ]Department of Neurology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland

Author notes

[∗ ]Corresponding author: David C. Henshall, PhD, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin D02 YN77, Ireland. dhenshall@ 123456rcsi.ie

Article

Publisher ID: S2162-2531(16)30359-6

DOI: 10.1016/j.omtn.2016.11.002

PMC ID: 5363384

PubMed ID: 28325299

SO-VID: 4df32921-7823-4cb1-9cd4-dbc9f0906b27

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 24 June 2016

Date accepted : 29 November 2016

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

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Most cited references 43

Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.

A brain-specific microRNA regulates dendritic spine development.

Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

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