Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model.

Shih-Yin Ho,Che-Wen Tsai,I-Chun Chen,Li Lin,Fang-Chia Chang,Horng-Huei Liou

doi:10.3389/fphar.2021.682767

Shih-Yin Ho, Che-Wen Tsai + Show 4 more

Open Access

https://doi.org/10.3389/fphar.2021.682767

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Abstract

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1a E1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1a E1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

Highlights

Dravet syndrome, known as severe myoclonic epilepsy in infancy, is a catastrophic and drugresistant epileptic encephalopathy, with an incidence of about 1 per 20,000 to 40,000 (Wu et al, 2015)
In an Scn1aE1099X/+ transgenic mouse model to simulate Dravet syndrome, PER decreased the occurrence of spontaneous recurrent seizures and when administered in combination with valproic acid or stiripentol had significant therapeutic effects on hyperthermia-induced seizures with regard to both susceptibility and severity
We believe our study is the first to assess the antiepileptic effects of PER combined with first-line antiepileptic drugs (AEDs) in a Dravet syndrome mouse model, which shows significant therapeutic potential on hyperthermia-induced seizures with regard to both susceptibility and severity

Summary

Introduction

Known as severe myoclonic epilepsy in infancy, is a catastrophic and drugresistant epileptic encephalopathy, with an incidence of about 1 per 20,000 to 40,000 (Wu et al, 2015). In addition to hyperthermia-induced epilepsy, patients with Dravet syndrome experience spontaneous recurrent seizures. 70–80% of Dravet syndrome patients have loss-of-function mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene (Marini et al, 2011). The protein encoded by this gene is voltage-gated sodium channel Nav1.1 which is predominantly expressed on the initial axon segment of the parvalbumin-positive gamma-aminobutyric acid (GABA) interneuron (Ogiwara et al, 2007). This genetic defect results in decreasing exocytosis of GABA from the axon terminal. Previous work in our and other laboratories supports the hypothesis that the mechanism of epileptogenesis in Dravet syndrome is insufficient GABA release leading to brain hyperexcitability (Yu et al, 2006; Ogiwara et al, 2007; Tsai et al, 2015)

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