TY - JOUR
T1 - Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy
AU - Reschke, Cristina R.
AU - Silva, Luiz F Almeida
AU - Norwood, Braxton A.
AU - Senthilkumar, Ketharini
AU - Morris, Gareth
AU - Sanz-Rodriguez, Amaya
AU - Conroy, Ronán M.
AU - Costard, Lara
AU - Neubert, Valentin
AU - Bauer, Sebastian
AU - Farrell, Michael A.
AU - O'Brien, Donncha F.
AU - Delanty, Norman
AU - Schorge, Stephanie
AU - Pasterkamp, R. Jeroen
AU - Rosenow, Felix
AU - Henshall, David C.
N1 - Funding Information:
The authors thank Eva Jimenez-Mateos and Tobias Engel for advice on technical aspects. The authors acknowledge funding from the Health Research Board Ireland (HRA-POR-2013-325 to D.C.H.) and Science Foundation Ireland (13/IA/1891 and 11/TIDA/B1988 to D.C.H.) and fellowships from the Brazilian National Council for Scientific and Technological Development (CNPq; to L.F.A.S.), the Royal Society (to S.S.), the Irish Research Council (to C.R.R.), CURE (Citizens United for Research in Epilepsy) (to B.A.N. and D.C.H.), and the European Union Seventh Framework Programme (FP7/2007?2013; under grant agreement 602130). They also gratefully acknowledge the NIH NeuroBioBank and the University of Maryland Brain and Tissue Bank for autopsy material. The role of the University of Maryland Brain and Tissue Bank is to distribute tissue, and therefore, it cannot endorse the studies performed or the interpretation of results.
Publisher Copyright:
© 2016 The Author(s)
PY - 2017/3/17
Y1 - 2017/3/17
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.
AB - 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 - anti-epileptic drug
KW - chemoconvulsant
KW - epileptogenesis
KW - hippocampal sclerosis
KW - noncoding RNA
KW - status epilepticus
KW - temporal lobe epilepsy
UR - https://www.scopus.com/pages/publications/85015651505
U2 - 10.1016/j.omtn.2016.11.002
DO - 10.1016/j.omtn.2016.11.002
M3 - Article
C2 - 28325299
AN - SCOPUS:85015651505
SN - 2162-2531
VL - 6
SP - 45
EP - 56
JO - Molecular therapy. Nucleic acids
JF - Molecular therapy. Nucleic acids
ER -