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  • Title: Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy.
    Author: Wengert ER, Saga AU, Panchal PS, Barker BS, Patel MK.
    Journal: Neuropharmacology; 2019 Nov 01; 158():107699. PubMed ID: 31278928.
    Abstract:
    SCN8A epileptic encephalopathy is a severe genetic epilepsy syndrome caused by de novo gain-of-function mutations of SCN8A encoding the voltage-gated sodium (Na) channel (VGSC) NaV1.6. Therapeutic management is difficult in many patients, leading to uncontrolled seizures and risk of sudden unexpected death in epilepsy (SUDEP). There is a need to develop novel anticonvulsants that can specifically target aberrant VGSC activity associated with SCN8A gain-of-function mutations. In this study, we investigate the effects of Prax330, a novel VGSC inhibitor, on the biophysical properties of wild-type (WT) NaV1.6 and the patient mutation p.Asn1768Asp (N1768D) in ND7/23 cells. The effects of Prax330 on persistent (INaP) and resurgent (INaR) Na currents and neuronal excitability in subiculum neurons from a knock-in mouse model of the Scn8a-N1768D mutation (Scn8aD/+) were also examined. In ND7/23 cells, Prax330 reduced INaP currents recorded from cells expressing Scn8a-N1768D and hyperpolarized steady-state inactivation curves. Recordings from brain slices demonstrated elevated INaP and INaR in subiculum neurons from Scn8aD/+ mutant mice and abnormally large action potential (AP) burst-firing events in a subset of neurons. Prax330 (1 μM) reduced both INaP and INaR and suppressed AP bursts, with a smaller effect on AP waveforms that had similar morphology to WT neurons. Prax330 (1 μM) also reduced synaptically-evoked APs in Scn8aD/+ subiculum neurons but not in WT neurons. Our results highlight the efficacy of targeting INaP and INaR and inactivation parameters in controlling subiculum excitability and suggest Prax330 as a promising novel therapy for SCN8A epileptic encephalopathy.
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