Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy. (1st November 2019)

• Record Type: Journal Article
• Authors: Wengert, Eric R.; Saga, Anusha U.; Panchal, Payal S.; Barker, Bryan S.; Patel, Manoj K.
• Is Part Of: Neuropharmacology. Volume 158(2019)
• Publication Date: 2019-11-01
• Subjects: Sodium channels -- Persistent sodium current -- Resurgent sodium current -- Prax330 -- Subiculum -- Epileptic encephalopathy -- SCN8A -- action potentials; Na Sodium -- INaT Transient current -- INaP Persistent Sodium Current -- INaR Resurgent Sodium Current -- AIS Axon initial segment -- AP Action potential -- VGSC voltage gated sodium channel; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107699
• Languages: English
• ISSNs: 0028-3908

Abstract

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) NaV 1.6. 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) NaV 1.6 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 ( Scn8a D/+ ) 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 Scn8a D/+ 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 Scn8a D /+ 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. Highlights: Pro-excitatory depolarizing shifts in N1768D steady-state inactivation curves and elevated persistent sodium currents are rescued by Prax330. Scn8a D/+ subiculum neurons expressing the N1768D mutation have elevated persistent and resurgent Na currents. Prax330 attenuates both persistent and resurgent Na currents of Scn8a D/+ subiculum neurons. Prax330 normalizes hyperpolarized threshold and suppresses aberrant bursting in Scn8a D/+ neurons. Prax330 reduces synaptically-evoked action potentials in neurons from Scn8a D /+, but not WT, mice.