AUTHOR=Satpute Janve Vaishali , Anderson Lyndsey L. , Bahceci Dilara , Hawkins Nicole A. , Kearney Jennifer A. , Arnold Jonathon C. 

TITLE=The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.675128

DOI=10.3389/fphar.2021.675128

ISSN=1663-9812

ABSTRACT=<p>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.<italic>Scn1a</italic><sup><italic>+/−</italic></sup> mouse model of DS. We found that cortical <italic>Trpv1</italic> mRNA expression was increased in seizure susceptible F1.<italic>Scn1a</italic><sup><italic>+/−</italic></sup> mice with a hybrid genetic background compared to seizure resistant 129.<italic>Scn1a</italic><sup><italic>+/−</italic></sup> mice isogenic on 129S6/SvEvTac background, suggesting <italic>Trpv1</italic> 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.<italic>Scn1a</italic><sup><italic>+/−</italic></sup> mice. Surprisingly, <italic>Trpv1</italic> deletion had both pro- and anti-seizure effects. <italic>Trpv1</italic> deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.<italic>Scn1a</italic><sup><italic>+/−</italic></sup>; <italic>Trpv1</italic><sup><italic>+/−</italic></sup> at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely, <italic>Trpv1</italic> deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest that <italic>Trpv1</italic> is a modest genetic modifier of spontaneous seizure severity in the F1.<italic>Scn1a</italic><sup><italic>+/−</italic></sup> model of DS. However, the opposing pro- and anti-seizure effects of <italic>Trpv1</italic> deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.</p>