Investigating the Therapeutic Mechanism of Cannabidiol in a Human Induced Pluripotent Stem Cell (iPSC)-Based Model of Dravet Syndrome.

Abstract

Dravet syndrome is an infantile epileptic encephalopathy primarily caused by loss-of-function variants of the gene SCN1A Standard treatment regimens have very limited efficacy to combat the life-threatening seizures in Dravet syndrome or the behavioral-cognitive comorbidities of the disease. Recently there has been encouraging progress in developing new treatments for this disorder. One of the clinical advances is cannabidiol (CBD), a compound naturally found in cannabis and shown to further reduce convulsive seizures in patients when used together with existing drug regimens. Like many other natural products, the exact therapeutic mechanism of CBD remains undefined. Previously we have established a human cellular model of Dravet syndrome by differentiating patient-derived induced pluripotent stem cells (iPSCs) into telencephalic inhibitory and excitatory neurons. Here we have applied this model to investigate the antiepileptic mechanism(s) of CBD at the cellular level. We first determined the effect of escalating the concentrations of CBD on neuronal excitability, using primary culture of rat cortical neurons. We found modulatory effects on excitability at submicromolar concentrations and toxic effects at high concentrations (15 µM). We then tested CBD at 50 nM, a concentration that corresponds to the estimated human clinical exposure, in telencephalic neurons derived from a patient iPSC line and control cell line H9. This 50 nM of CBD increased the excitability of inhibitory neurons but decreased the excitability of excitatory neurons, without changing the amplitude of sodium currents in either cell type. Our findings suggest a cell type-dependent mechanism for the therapeutic action of CBD in Dravet syndrome that is independent of sodium channel activity.