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 UnionSeventh Framework Programme (FP7/2007–2013; under grant agreement 602130).
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.
Physics | Physiology
Reschke CR, Silva LF, Norwood BA, Senthilkumar K, Morris G, Sanz-Rodriguez A, Conroy RM, Costard L, Neubert V, Bauer S, Farrell MA, O'Brien DF, Delanty N, Schorge S, Pasterkamp RJ, Rosenow F, Henshall DC. Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy.Molecular Therapy Nucleic Acids. 2017;6:45-56
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