Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice

Qays Kharouf; Paulo Pinares-Garcia; M Novella Romanelli; Christopher A Reid

doi:10.1016/j.eplepsyres.2020.106484

Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice

Epilepsy Res. 2020 Dec:168:106484. doi: 10.1016/j.eplepsyres.2020.106484. Epub 2020 Oct 10.

Authors

Qays Kharouf¹, Paulo Pinares-Garcia², M Novella Romanelli³, Christopher A Reid⁴

Affiliations

¹ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
² Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
³ Department of Neurosciences, Psichology, Drug Research and Child Health, (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, I-50019, Sesto Fiorentino, Italy.
⁴ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. Electronic address: careid@unimelb.edu.au.

PMID: 33099130
DOI: 10.1016/j.eplepsyres.2020.106484

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated in the pathogenesis of epilepsy and consequently as targets for anticonvulsant drugs. Consistent with this, broad-spectrum block of HCN-mediated current (I_h) reduces seizure susceptibility in a variety of epilepsy models. However, HCN channel isoforms have distinct biophysical characteristics and anatomical expression suggesting that they may play different roles in setting neuronal excitability. Here we confirm that the broad-spectrum blocker ivabradine is effective at reducing seizure susceptibility in the s.c.PTZ seizure assay and extend this, showing efficacy of this drug in a thermogenic assay that models febrile seizures. Ivabradine is also effective at reducing thermogenic seizures in the Scn1a mouse model of Dravet syndrome in which febrile seizures are a feature. HCN isoform-preferring drugs were tested in the s.c.PTZ seizure assay. We confirm that the HCN4-preferring drug, EC18, is efficacious in reducing seizure susceptibility. Conversely, the HCN2/1-preferring drug, MEL55A, increased seizure susceptibility in the s.c.PTZ seizure assay. MEL57A, an HCN1-preferring drug, had no effect on seizure susceptibility. Mouse pharmacokinetic studies (for MEL55A and MEL57A) and screening against additional ion channels have not been thoroughly investigated on the HCN isoform-preferring compounds. Our results need to be considered in this light. Nevertheless, these data suggest that HCN isoform-selective block can have a differential impact on seizure susceptibility. This motivates the need to develop more HCN isoform-selective compounds to better explore this idea.

Keywords: Anticonvulsant; Drug target; HCN channel block; Hyperpolarization-activated cyclic nucleotide-gated channels; Ion channels; Neuronal excitability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anticonvulsants / pharmacology*
Benzazepines / pharmacology*
Cyclic Nucleotide-Gated Cation Channels / drug effects*
Cyclic Nucleotide-Gated Cation Channels / metabolism
Disease Models, Animal
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / drug effects*
Male
Mice, Inbred C57BL
Neurons / drug effects
Neurons / metabolism
Potassium Channels / drug effects
Potassium Channels / metabolism
Protein Isoforms / metabolism

Substances

Anticonvulsants
Benzazepines
Cyclic Nucleotide-Gated Cation Channels
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
N,N-bis-((Z)-4-(7,8-dimethoxy-2-oxo-1,3-dihydrobenzo(d)azepin-3-yl)but-2-enyl)-2-(3,4-dimethoxyphenyl)-propanamine
Potassium Channels
Protein Isoforms