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

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    Author
    Kharouf, Q; Pinares-Garcia, P; Romanelli, MN; Reid, CA
    Date
    2020-12-01
    Source Title
    Epilepsy Research
    Publisher
    ELSEVIER
    University of Melbourne Author/s
    Reid, Christopher; Kharouf, Qays
    Affiliation
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Kharouf, Q., Pinares-Garcia, P., Romanelli, M. N. & Reid, C. A. (2020). Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice. EPILEPSY RESEARCH, 168, https://doi.org/10.1016/j.eplepsyres.2020.106484.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/254132
    DOI
    10.1016/j.eplepsyres.2020.106484
    Open Access URL
    https://flore.unifi.it/bitstream/2158/1209972/1/137_Epilepsy2020_reid.pdf
    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 (Ih) 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.

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