Channelopathy of Dravet Syndrome and Potential Neuroprotective Effects of Cannabidiol

Abstract

Dravet syndrome (DS) is a channelopathy, neurodevelopmental, epileptic encephalopathy characterized by seizures, developmental delay, and cognitive impairment that includes susceptibility to thermally induced seizures, spontaneous seizures, ataxia, circadian rhythm and sleep disorders, autistic-like behaviors, and premature death. More than 80% of DS cases are linked to mutations in genes which encode voltage-gated sodium channel subunits, SCN1A and SCN1B, which encode the Nav1.1α subunit and Nav1.1β1 subunit, respectively. There are other gene mutations encoding potassium, calcium, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels related to DS. One-third of patients have pharmacoresistance epilepsy. DS is unresponsive to standard therapy. Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been introduced for treating DS because of its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. However, the etiological channelopathiological mechanism of DS and action mechanism of CBD on the channels are unclear. In this review, we summarize evidence of the direct and indirect action mechanism of sodium, potassium, calcium, and HCN channels in DS, especially sodium subunits. Some channels’ loss-of-function or gain-of-function in inhibitory or excitatory neurons determine the balance of excitatory and inhibitory are associated with DS. A great variety of mechanisms of CBD anticonvulsant effects are focused on modulating these channels, especially sodium, calcium, and potassium channels, which will shed light on ionic channelopathy of DS and the precise molecular treatment of DS in the future.

The Genetic Facets of Dravet Syndrome: Recent Insights

“…It is clear that DS predominantly arises from diminished NaV1.1 functionality due to haploinsufficiency. Mutations in the SCN1A gene disrupt the balance between neuronal excitation and inhibition in the brain, leading to epileptic seizures and other symptoms of DS [25]. Electrophysiological scrutiny of DS-linked missense variants underscores their tendency to provoke loss-of-function alterations, often rendering channels nonfunctional.…”

“…CBD is a non-psychoactive compound derived from cannabis plants. Several studies [25,98], have reported that CBD use led to a significant reduction in seizure frequency in patients with DS. CBD is believed to exert its antiepileptic effects through multiple mechanisms, including modulation of neuronal excitability and inflammation.…”

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

“…Xu et al summarized evidence on the direct and indirect mechanisms of action of sodium, potassium, and HCN channels in Dravet syndrome and understanding the application of CBD, whose antiepileptic effects enable modulation of these channels [ 103 ]. CBD has demonstrated neuroprotective effects in experimental animal models of Dravet syndrome as well as clinical data.…”

Identification of Novel and De Novo Mutation in the SCN1A Gene By Exome Sequencing Confirms Dravet Syndrome in Moroccan Child: A Case Report

“…Despite advances in understanding the genetic and molecular basis of DS, there is still no cure for the condition, and current treatment options focus on seizure control and management of associated symptoms (8,24). Conventional antiepileptic drugs (AEDs) are often ineffective in controlling seizures in individuals with DS, and multiple drug therapies, such as a combination of sodium channel blockers and other AEDs, are often required (8,25).…”