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

ABSTRACT: 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.

SUBMITTER: Reschke CR

PROVIDER: S-EPMC5363384 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Reschke Cristina R CR Silva Luiz F Almeida LFA Norwood Braxton A BA Senthilkumar Ketharini K Morris Gareth G Sanz-Rodriguez Amaya A Conroy Ronán M RM Costard Lara L Neubert Valentin V Bauer Sebastian S Farrell Michael A MA O'Brien Donncha F DF Delanty Norman N Schorge Stephanie S Pasterkamp R Jeroen RJ Rosenow Felix F Henshall David C DC

Molecular therapy. Nucleic acids 20161210

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), ch ...[more]

PMID: 28325299

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Project description:Background: OLFM3 (olfactomedin-3) is a member of the olfactomedin domain family, which has been found to stimulate the formation and adhesion of tight cell connections and to regulate cytoskeleton formation and cell migration. Differences in the gene coding for OLFM3 have been found between patients with epilepsy and controls. However, the exact role of OLFM3 in epilepsy has not been thoroughly investigated. Methods: Biochemical methods were used to assess OLFM3 expression and localization in the cortex of patients with temporal lobe epilepsy and in the hippocampus and cortex of epileptic mice. Electrophysiological recordings were used to measure the role of OLFM3 in regulating hippocampal excitability in a model of magnesium-free-induced seizure in vitro. Behavioral experiments were performed in a pentylenetetrazol (PTZ)-induced seizure model, and electroencephalograms (EEGs) were recorded in the chronic phase of the kainic acid (KA)-induced epilepsy model in vivo. OLFM3 and its interaction with AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor) subunits were analyzed by co-immunoprecipitation. Results: The expression of OLFM3 was increased in the cortex of patients with temporal lobe epilepsy and in the hippocampus and cortex of epileptic mice compared with controls. Interestingly, lentivirus-mediated overexpression of OLFM3 in the hippocampus increased the susceptibility of mice to PTZ-induced seizures, and OLFM3 knockdown had the opposite effect. OLFM3 affected AMPAR currents in a brain-slice model of epileptiform activity induced by Mg2+-free medium. We found that OLFM3 co-immunoprecipitation with GluA1 and GluA2. Furthermore, downregulation or overexpression of OLFM3 in the hippocampus affected the membrane expression of GluA1 and GluA2 in epileptic mice. Conclusion: These findings reveal that OLFM3 may enhance seizure activity by interacting with GluA1 and GluA2, potentially indicating a molecular mechanism for new therapeutic strategies.

Dataset Information

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

Publications

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

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