Abstract
Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a +/− mouse model of DS. We found that cortical Trpv1 mRNA expression was increased in seizure susceptible F1.Scn1a +/− mice with a hybrid genetic background compared to seizure resistant 129.Scn1a +/− mice isogenic on 129S6/SvEvTac background, suggesting Trpv1 could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a +/− mice. Surprisingly, Trpv1 deletion had both pro- and anti-seizure effects. Trpv1 deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a +/−; Trpv1 +/− at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely, Trpv1 deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest that Trpv1 is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a +/− model of DS. However, the opposing pro- and anti-seizure effects of Trpv1 deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.
Highlights
Dravet syndrome (DS) is a catastrophic early onset epileptic encephalopathy that typically begins with febrile seizures and progresses into numerous spontaneous afebrile seizures that are poorly managed by currently available anticonvulsant drugs (Scheffer et al, 2017)
To determine whether Trpv1 expression may contribute to the epilepsy phenotype of Scn1a+/− mice, we compared the cortical mRNA levels from WT and Scn1a+/− mice on both 129S6/ SvEvTac (129) and on [129S6/SvEvTac × C57BL/6J]F1 (129 × B6) genetic backgrounds
We first sought to pharmacologically evaluate whether Trpv1 is a viable drug target in the F1.Scn1a+/− mice by assessing the effects of the selective Trpv1 antagonist SB-705498 against hyperthermia-induced seizures, spontaneous seizures, and survival of the F1.Scn1a+/− mice
Summary
Dravet syndrome (DS) is a catastrophic early onset epileptic encephalopathy that typically begins with febrile seizures and progresses into numerous spontaneous afebrile seizures that are poorly managed by currently available anticonvulsant drugs (Scheffer et al, 2017). Scn1a+/− mice on the 129S6/SvEvTac background (129.Scn1a+/−) are seizure resistant and do not display an overt seizure phenotype, while those on the [129S6/SvEvTac × C57BL/6J]F1 background (F1.Scn1a+/−) are seizure-susceptible and display a severe seizure phenotype with premature mortality (Miller et al, 2014). This strain-dependent phenotype severity suggests that the introduction of the C57BL/6J genetic background modifies the impact of the heterozygous deletion of Scn1a, and enhances the expressivity of the severe seizure phenotype. Potential modifier genes can be inferred by comparing the coding sequence and expression of a candidate gene between seizure susceptible and seizure resistant mouse strains
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