Effects of the Ih Blockers CsCl and ZD7288 on Inherited Epilepsy in Mongolian Gerbils

Matsuda, Yoshiki; Saito, Noriko; Yamamoto, Kiyofumi; Niitsu, Takashi; Kogure, Shinichi

doi:10.1538/expanim.57.377

Cited by 8 publications

(5 citation statements)

References 45 publications

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“…Broad-spectrum block with ZD7288 also reduces seizure susceptibility in several animal models of epilepsy including electrically induced paroxysmal discharges ( Kitayama et al, 2003 ), generalized seizures in Mongolian gerbils ( Matsuda et al, 2008 ), and maximal electroshock-induced seizures ( Luszczki et al, 2013 ). There is some associative evidence suggesting increased HCN4 channel function may be part of the mechanism underlying hyperexcitability in epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Gabapentin Modulates HCN4 Channel Voltage-Dependence

et al. 2017

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Gabapentin (GBP) is widely used to treat epilepsy and neuropathic pain. There is evidence that GBP can act on hyperpolarization-activated cation (HCN) channel-mediated Ih in brain slice experiments. However, evidence showing that GBP directly modulates HCN channels is lacking. The effect of GBP was tested using two-electrode voltage clamp recordings from human HCN1, HCN2, and HCN4 channels expressed in Xenopus oocytes. Whole-cell recordings were also made from mouse spinal cord slices targeting either parvalbumin positive (PV+) or calretinin positive (CR+) inhibitory neurons. The effect of GBP on Ih was measured in each inhibitory neuron population. HCN4 expression was assessed in the spinal cord using immunohistochemistry. When applied to HCN4 channels, GBP (100 μM) caused a hyperpolarizing shift in the voltage of half activation (V1/2) thereby reducing the currents. Gabapentin had no impact on the V1/2 of HCN1 or HCN2 channels. There was a robust increase in the time to half activation for HCN4 channels with only a small increase noted for HCN1 channels. Gabapentin also caused a hyperpolarizing shift in the V1/2 of Ih measured from HCN4-expressing PV+ inhibitory neurons in the spinal dorsal horn. Gabapentin had minimal effect on Ih recorded from CR+ neurons. Consistent with this, immunohistochemical analysis revealed that the majority of CR+ inhibitory neurons do not express somatic HCN4 channels. In conclusion, GBP reduces HCN4 channel-mediated currents through a hyperpolarized shift in the V1/2. The HCN channel subtype selectivity of GBP provides a unique tool for investigating HCN4 channel function in the central nervous system. The HCN4 channel is a candidate molecular target for the acute analgesic and anticonvulsant actions of GBP.

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Section: Discussionmentioning

confidence: 99%

Gabapentin Modulates HCN4 Channel Voltage-Dependence

et al. 2017

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“…At a genetic level, both gain‐ and loss‐of‐function HCN1 variants, as measured in heterologous expression assays, associate with epilepsy (Marini et al, 2018; Nava et al, 2014). Pharmacologically, the broad‐spectrum I h blockers ivabradine, caesium and ZD7288 all have anticonvulsant activity in seizure models (Kitayama et al, 2003; Luszczki, Prystupa, Andres‐Mach, Marzeda, & Florek‐Luszczki, 2013; Matsuda, Saito, Yamamoto, Niitsu, & Kogure, 2008). Together, these data suggest that HCN channels, as a class, are important modulators of neuronal excitability in epilepsy.…”

Section: Introductionmentioning

confidence: 99%

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

Kharouf

Phillips

Bleakley

et al. 2020

British J Pharmacology

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Background and Purpose Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are encoded by four genes (HCN1–4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalization. Here, we assessed the utility of targeting the HCN4 channel as an anti‐seizure strategy using pharmacological and genetic approaches. Experimental Approach The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using an HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model. Key Results EC18 (10 mg·kg−1) and brain‐specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant‐mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10 μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant‐mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV‐HCN4 shRNA infected mouse cortical cultures. Conclusions and Implications These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti‐seizure drugs that is likely to have a low side‐effect liability in the CNS.

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“…These include the efficacy of HCN channel blockers in s.c.PTZ and kainate seizure models, as well as the MES model of epilepsy (Cavalcante et al, 2019;Luszczki et al, 2013;Mansour and Ibrahim, 2015). Furthermore, other broad-spectrum I h blockers reduce the rate of spontaneous seizures in the seizure-sensitive Mongolian gerbil (Matsuda et al, 2008) and increased the threshold to stimulus-evoked paroxysmal discharges in the rabbit hippocampal CA1 region (Kitayama et al, 2003). Here we have extended this to include efficacy of ivabradine in a thermogenic assay that models febrile seizures.…”

Section: The Impact Of Isoform-preferring Hcn Channel Blockers On Seimentioning

confidence: 97%

“…ZD7288-mediated I h block has been shown to prevent formation of epileptiform discharges in rat hippocampal CA1 and CA3 regions (Xiong and Stringer, 1999). Furthermore, CsCl and ZD7288 decrease the severity and frequency of spontaneous seizures in the seizure-sensitive Mongolian gerbil (Matsuda et al, 2008). The FDA approved drug, ivabradine, is used clinically for the treatment of chronic stable angina and chronic heart failure (Ide et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Effects of the Ih Blockers CsCl and ZD7288 on Inherited Epilepsy in Mongolian Gerbils

Abstract: 0.99 ± 0.07 before administration, 0.52 ± 0.06 (P<0.01) during administration, and 0.76 ± 0.07 (P<0.05)

Cited by 8 publications

References 45 publications

Gabapentin Modulates HCN4 Channel Voltage-Dependence

Gabapentin Modulates HCN4 Channel Voltage-Dependence

The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target

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

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