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

Autor:	Reschke CR; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Silva LFA; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Norwood BA; Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany., Senthilkumar K; 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., Morris G; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, London WC1N 3BG, UK., Sanz-Rodriguez A; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Conroy RM; Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland., Costard L; Department of Neurology, Philipps University, Marburg 35043, Germany., Neubert V; Department of Neurology, Philipps University, Marburg 35043, Germany., Bauer S; Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany., Farrell MA; Department of Pathology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland., O'Brien DF; Department of Neurological Surgery, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland., Delanty N; Department of Neurology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland., Schorge S; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, London WC1N 3BG, UK., Pasterkamp RJ; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands., Rosenow F; Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany., Henshall DC; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland. Electronic address: dhenshall@rcsi.ie.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2017 Mar 17; Vol. 6, pp. 45-56. Date of Electronic Publication: 2016 Dec 10.
DOI:	10.1016/j.omtn.2016.11.002
Abstrakt:	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. (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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