Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy.
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.
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.
Cristina R
CR
Reschke
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.
Luiz F Almeida
LFA
Silva
Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany.
Braxton A
BA
Norwood
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.
Ketharini
K
Senthilkumar
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, London WC1N 3BG, UK.
Gareth
G
Morris
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.
Amaya
A
Sanz-Rodriguez
Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.
Ronán M
RM
Conroy
Department of Neurology, Philipps University, Marburg 35043, Germany.
Lara
L
Costard
Department of Neurology, Philipps University, Marburg 35043, Germany.
Valentin
V
Neubert
Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany.
Sebastian
S
Bauer
Department of Pathology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland.
Michael A
MA
Farrell
Department of Neurological Surgery, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland.
Donncha F
DF
O'Brien
Department of Neurology, Beaumont Hospital, Beaumont, Dublin D09 C562, Ireland.
Norman
N
Delanty
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, London WC1N 3BG, UK.
Stephanie
S
Schorge
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
R Jeroen
RJ
Pasterkamp
Department of Neurology, Philipps University, Marburg 35043, Germany; Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt 60528, Germany.
Felix
F
Rosenow
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland. Electronic address: dhenshall@rcsi.ie.
David C
DC
Henshall
anti-epileptic drug; chemoconvulsant; epileptogenesis; hippocampal sclerosis; noncoding RNA; status epilepticus; temporal lobe epilepsy