TY  - JOUR
A1  - Reschke, Cristina R.
A1  - Almeida Silva, Luiz F.
A1  - Norwood, Braxton A.
A1  - Senthilkumar, Ketharini
A1  - Morris, Gareth
A1  - Sanz-Rodriguez, Amaya
A1  - Conroy, Ronan M.
A1  - Costard, Lara
A1  - Neubert, Valentin
A1  - Bauer, Sebastian
A1  - Farrell, Michael A.
A1  - O'Brien, Donncha F.
A1  - Delanty, Norman
A1  - Schorge, Stephanie
A1  - Pasterkamp, Ronald Jeroen
A1  - Rosenow, Felix
A1  - Henshall, David C.
T1  - Potent anti-seizure effects of locked nucleic acid antagomirs targeting miR-134 in multiple mouse and rat models of epilepsy
T2  - Molecular therapy. Nucleic Acids
N2  - 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.
KW  - noncoding RNA
KW  - hippocampal sclerosis
KW  - epileptogenesis
KW  - chemoconvulsant
KW  - status epilepticus
KW  - anti-epileptic drug
KW  - temporal lobe epilepsy
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/43173
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-431735
SN  - 2162-2531
N1  - © 2016 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
VL  - 6
SP  - 45
EP  - 56
PB  - Nature Publ. Group
CY  - New York, NY
ER  -