Use-Dependent Block of Human Cardiac Sodium Channels by GS967

Potet, F; Vanoye, Carlos G.; George, Alfred L.

doi:10.1124/mol.116.103358

Cited by 36 publications

(36 citation statements)

References 31 publications

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“…We and others previously reported that GS967 is a potent inhibitor of persistent sodium current, with 9‐fold greater potency than phenytoin in hippocampal pyramidal neurons from Scn2a Q54 mice . Consistent with these reports, acute application of 200 nmol·L –1 GS967 or 4 μmol·L –1 phenytoin to acutely dissociated hippocampal neurons isolated from Scn8a D/+ mice resulted in inhibition of persistent sodium current without significantly affecting peak current.…”

Section: Discussionsupporting

confidence: 85%

“…Symbols represent mean AE standard error of the mean because poor seizure control and frequent, prolonged generalized tonic-clonic seizures are major risk factors for SUDEP. 35 GS967 was originally developed as an antiarrhythmic compound, 22,24,32,33 and may also have a direct effect on the heart. This effect may contribute to the protection against sudden death, because Scn8a D/+ mice have hyperexcitable cardiomyocytes, and episodes of bradycardia have been observed in electrocardiograms.…”

Section: Anticonvulsant Activity Of Gs967mentioning

confidence: 99%

“…Our previous studies demonstrated that acute application of GS967 to hippocampal neurons did not affect the current‐voltage relationship or voltage dependence of activation, but induced a hyperpolarized shift of steady‐state channel inactivation and slowed both recovery from fast inactivation and onset of slow inactivation . GS967 has also been reported to have strong use‐dependent block …”

Section: Introductionmentioning

confidence: 99%

“…23 GS967 has also been reported to have strong use-dependent block. 24 GS967 was previously tested in the Scn2a Q54 mouse model with epilepsy caused by elevated persistent sodium current in hippocampal neurons. 25 Acute application of GS967 to neurons isolated from untreated Scn2a Q54 mice reduced persistent sodium current and spontaneous firing, and GS967 treatment of Scn2a Q54 mice reduced seizure burden and improved survival.…”

Section: Introductionmentioning

confidence: 99%

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The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

Thompson

Hawkins

et al. 2018

Epilepsia

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Section: Discussionsupporting

confidence: 85%

Section: Anticonvulsant Activity Of Gs967mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

Thompson

Hawkins

et al. 2018

Epilepsia

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“…However, we recently discovered additional biophysical effects of this compound on heterologously expressed cardiac sodium channels 28 . Similarly in this study, we demonstrated significant effects of GS967 on neuronal sodium current including a potent stabilization of inactivation leading to strong use-dependent block (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Anderson

Hawkins

Thompson

et al. 2017

Sci Rep

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Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a +/−) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model. Because clinical observations suggest conventional sodium channel blocking antiepileptic drugs may worsen the disease, we predicted the phenotype of Scn1a +/− mice would be exacerbated by GS967, a potent, unconventional sodium channel blocker. Unexpectedly, GS967 significantly improved survival of Scn1a +/− mice and suppressed spontaneous seizures. By contrast, lamotrigine exacerbated the seizure phenotype. Electrophysiological recordings of acutely dissociated neurons revealed that chronic GS967-treatment had no impact on evoked action potential firing frequency of interneurons, but did suppress aberrant spontaneous firing of pyramidal neurons and was associated with significantly lower sodium current density. Lamotrigine had no effects on neuronal excitability of either neuron subtype. Additionally, chronically GS967-treated Scn1a +/− mice exhibited normalized pyramidal neuron sodium current density and reduced hippocampal NaV1.6 protein levels, whereas lamotrigine treatment had no effect on either pyramidal neuron sodium current or hippocampal NaV1.6 levels. Our findings demonstrate unexpected efficacy of a novel sodium channel blocker in Dravet syndrome and suggest a potential mechanism involving a secondary change in NaV1.6.

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Genomic Autopsy of Sudden Deaths in Young Individuals

et al. 2021

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IMPORTANCEPostmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information.OBJECTIVE To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families.DESIGN, SETTING, AND PARTICIPANTS Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020.EXPOSURES Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation.RESULTS A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex-and genetic ancestry-matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, −1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant.CONCLUSIONS AND RELEVANCE Whole-genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.

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Use-Dependent Block of Human Cardiac Sodium Channels by GS967

Cited by 36 publications

References 31 publications

The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Genomic Autopsy of Sudden Deaths in Young Individuals

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