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

Cristina R. Reschke; Luiz F. Almeida Silva; Braxton A. Norwood; K Senthilkumar; G Morris; A Sanz-Rodriguez; Ronán M. Conroy; L Costard; V Neubert; S Bauer; Michael A. Farrell; Donncha F. O’Brien; N Delanty; S Schorge; R. Jeroen Pasterkamp; F Rosenow; David C. Henshall

doi:10.1016/j.omtn.2016.11.002

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

Cristina R. Reschke
, Luiz F. Almeida Silva
, Braxton A. Norwood
, K Senthilkumar
, G Morris
, A Sanz-Rodriguez
, Ronán M. Conroy
, L Costard
, V Neubert
, S Bauer
, Michael A. Farrell
, Donncha F. O’Brien
, N Delanty
, S Schorge
, R. Jeroen Pasterkamp
, F Rosenow
, David C. Henshall^*

^*Corresponding author for this work

Division of Neuroscience

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	45-56
Number of pages	12
Journal	Molecular Therapy
Early online date	26 Jan 2017
DOIs	https://doi.org/10.1016/j.omtn.2016.11.002
Publication status	Published - 17 Mar 2017

Keywords

noncoding RNA
hippocampal sclerosis
epileptogenesis
chemoconvulsant
status epilepticus
anti-epileptic drug
temporal lobe epilepsy

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Reschke, C. R., Almeida Silva, L. F., Norwood, B. A., Senthilkumar, K., Morris, G., Sanz-Rodriguez, A., Conroy, R. M., Costard, L., Neubert, V., Bauer, S., Farrell, M. A., O’Brien, D. F., Delanty, N., Schorge, S., Pasterkamp, R. J., Rosenow, F., & Henshall, D. C. (2017). Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy. Molecular Therapy, 45-56. https://doi.org/10.1016/j.omtn.2016.11.002

@article{1ebfcdc9fe254fcb9d88d26ebf27e338,

title = "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.",

keywords = "noncoding RNA, hippocampal sclerosis, epileptogenesis, chemoconvulsant, status epilepticus, anti-epileptic drug, temporal lobe epilepsy",

author = "Reschke, \{Cristina R.\} and \{Almeida Silva\}, \{Luiz F.\} and Norwood, \{Braxton A.\} and K Senthilkumar and G Morris and A Sanz-Rodriguez and Conroy, \{Ron{\'a}n M.\} and L Costard and V Neubert and S Bauer and Farrell, \{Michael A.\} and O{\textquoteright}Brien, \{Donncha F.\} and N Delanty and S Schorge and Pasterkamp, \{R. Jeroen\} and F Rosenow and Henshall, \{David C.\}",

year = "2017",

month = mar,

day = "17",

doi = "10.1016/j.omtn.2016.11.002",

language = "English",

pages = "45--56",

journal = "Molecular Therapy",

issn = "1525-0016",

publisher = "Cell Press",

}

Reschke, CR, Almeida 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 2017, 'Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy', Molecular Therapy, pp. 45-56. https://doi.org/10.1016/j.omtn.2016.11.002

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 - Almeida Silva, Luiz F.

AU - Norwood, Braxton A.

AU - Senthilkumar, K

AU - Morris, G

AU - Sanz-Rodriguez, A

AU - Conroy, Ronán M.

AU - Costard, L

AU - Neubert, V

AU - Bauer, S

AU - Farrell, Michael A.

AU - O’Brien, Donncha F.

AU - Delanty, N

AU - Schorge, S

AU - Pasterkamp, R. Jeroen

AU - Rosenow, F

AU - Henshall, David C.

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 - noncoding RNA

KW - hippocampal sclerosis

KW - epileptogenesis

KW - chemoconvulsant

KW - status epilepticus

KW - anti-epileptic drug

KW - temporal lobe epilepsy

UR - http://europepmc.org/abstract/med/28325299

U2 - 10.1016/j.omtn.2016.11.002

DO - 10.1016/j.omtn.2016.11.002

M3 - Article

C2 - 28325299

SN - 1525-0016

SP - 45

EP - 56

JO - Molecular Therapy

JF - Molecular Therapy

ER -

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

Abstract

Keywords

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