Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol

Reesha R. Patel, Cindy Barbosa, Tatiana Brustovetsky, Nikolai Broustovetski, Theodore Cummins

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Mutations in brain isoforms of voltage-gated sodium channels have been identified in patients with distinct epileptic phenotypes. Clinically, these patients often do not respond well to classic anti-epileptics and many remain refractory to treatment. Exogenous as well as endogenous cannabinoids have been shown to target voltage-gated sodium channels and cannabidiol has recently received attention for its potential efficacy in the treatment of childhood epilepsies. In this study, we further investigated the ability of cannabinoids to modulate sodium currents from wild-type and epilepsy-associated mutant voltage-gated sodium channels. We first determined the biophysical consequences of epilepsy-associated missense mutations in both Nav1.1 (arginine 1648 to histidine and asparagine 1788 to lysine) and Nav1.6 (asparagine 1768 to aspartic acid and leucine 1331 to valine) by obtaining whole-cell patch clamp recordings in human embryonic kidney 293T cells with 200 μM Navβ4 peptide in the pipette solution to induce resurgent sodium currents. Resurgent sodium current is an atypical near threshold current predicted to increase neuronal excitability and has been implicated in multiple disorders of excitability. We found that both mutations in Nav1.6 dramatically increased resurgent currents while mutations in Nav1.1 did not. We then examined the effects of anandamide and cannabidiol on peak transient and resurgent currents from wild-type and mutant channels. Interestingly, we found that cannabidiol can preferentially target resurgent sodium currents over peak transient currents generated by wild-type Nav1.6 as well as the aberrant resurgent and persistent current generated by Nav1.6 mutant channels. To further validate our findings, we examined the effects of cannabidiol on endogenous sodium currents from striatal neurons, and similarly we found an inhibition of resurgent and persistent current by cannabidiol. Moreover, current clamp recordings show that cannabidiol reduces overall action potential firing of striatal neurons. These findings suggest that cannabidiol could be exerting its anticonvulsant effects, at least in part, through its actions on voltage-gated sodium channels, and resurgent current may be a promising therapeutic target for the treatment of epilepsy syndromes.

Original languageEnglish (US)
Pages (from-to)2164-2181
Number of pages18
JournalBrain
Volume139
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Cannabidiol
Sodium Channels
Epilepsy
Voltage-Gated Sodium Channels
Sodium
Corpus Striatum
Cannabinoids
Asparagine
Mutation
Neurons
HEK293 Cells
Valine
Missense Mutation
Histidine
Aspartic Acid
Leucine
Anticonvulsants
Action Potentials
Lysine
Arginine

Keywords

  • cannabidiol
  • Dravet syndrome
  • GEFS+
  • resurgent current
  • VGSC

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. / Patel, Reesha R.; Barbosa, Cindy; Brustovetsky, Tatiana; Broustovetski, Nikolai; Cummins, Theodore.

In: Brain, Vol. 139, No. 8, 01.08.2016, p. 2164-2181.

Research output: Contribution to journalArticle

Patel, Reesha R. ; Barbosa, Cindy ; Brustovetsky, Tatiana ; Broustovetski, Nikolai ; Cummins, Theodore. / Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. In: Brain. 2016 ; Vol. 139, No. 8. pp. 2164-2181.
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