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

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

Molecular Therapy: Nucleic Acids (Mar 2017)

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

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

Affiliations

Cristina R. Reschke: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland
Luiz F. Almeida Silva: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland
Braxton A. Norwood: Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany
Ketharini Senthilkumar: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands
Gareth Morris: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, London WC1N 3BG, UK
Amaya Sanz-Rodriguez: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland
Ronán M. Conroy: Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland
Lara Costard: Department of Neurology, Philipps University, Marburg 35043, Germany
Valentin Neubert: Department of Neurology, Philipps University, Marburg 35043, Germany
Sebastian Bauer: Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany
Michael A. Farrell: Department of Pathology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland
Donncha F. O’Brien: Department of Neurological Surgery, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland
Norman Delanty: Department of Neurology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland
Stephanie Schorge: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, London WC1N 3BG, UK
R. Jeroen Pasterkamp: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands
Felix Rosenow: Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany
David C. Henshall: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland; 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.

Journal volume & issue: Vol. 6
pp. 45 – 56

Abstract

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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. Keywords: noncoding RNA, hippocampal sclerosis, epileptogenesis, chemoconvulsant, status epilepticus, anti-epileptic drug, temporal lobe epilepsy

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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