The endocannabinoid system impacts seizures in a mouse model of Dravet syndrome

Neuropharmacology. 2022 Mar 1:205:108897. doi: 10.1016/j.neuropharm.2021.108897. Epub 2021 Nov 22.

Abstract

Dravet syndrome is a catastrophic childhood epilepsy with multiple seizure types that are refractory to treatment. The endocannabinoid system regulates neuronal excitability so a deficit in endocannabinoid signaling could lead to hyperexcitability and seizures. Thus, we sought to determine whether a deficiency in the endocannabinoid system might contribute to seizure phenotypes in a mouse model of Dravet syndrome and whether enhancing endocannabinoid tone is anticonvulsant. Scn1a+/- mice model the clinical features of Dravet syndrome: hyperthermia-induced seizures, spontaneous seizures and reduced survival. We examined whether Scn1a+/- mice exhibit deficits in the endocannabinoid system by measuring brain cannabinoid receptor expression and endocannabinoid concentrations. Next, we determined whether pharmacologically enhanced endocannabinoid tone was anticonvulsant in Scn1a+/- mice. We used GAT229, a positive allosteric modulator of the cannabinoid (CB1) receptor, and ABX-1431, a compound that inhibits the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). The Scn1a+/- phenotype is strain-dependent with mice on a 129S6/SvEvTac (129) genetic background having no overt phenotype and those on an F1 (129S6/SvEvTac x C57BL/6J) background exhibiting a severe epilepsy phenotype. We observed lower brain cannabinoid CB1 receptor expression in the seizure-susceptible F1 compared to seizure-resistant 129 strain, suggesting an endocannabinoid deficiency might contribute to seizure susceptibility. GAT229 and ABX-1431 were anticonvulsant against hyperthermia-induced seizures. However, subchronic ABX1431 treatment increased spontaneous seizure frequency despite reducing seizure severity. Cnr1 is a putative genetic modifier of epilepsy in the Scn1a+/- mouse model of Dravet syndrome. Compounds that increase endocannabinoid tone could be developed as novel treatments for Dravet syndrome.

Keywords: Cannabinoid receptor; Dravet syndrome; Endocannabinoid system; Epilepsy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology*
  • Cannabinoid Receptor Agonists / pharmacology*
  • Disease Models, Animal
  • Endocannabinoids / antagonists & inhibitors*
  • Endocannabinoids / deficiency
  • Endocannabinoids / metabolism*
  • Epilepsies, Myoclonic / drug therapy*
  • Epilepsies, Myoclonic / metabolism*
  • Indoles / pharmacology
  • Mice
  • Mice, 129 Strain
  • Mice, Transgenic
  • Piperazines / pharmacology
  • Pyrrolidines / pharmacology
  • Receptor, Cannabinoid, CB1 / agonists*

Substances

  • 3-(2-nitro-1-phenylethyl)-2-phenyl-1H-indole
  • ABX-1431
  • Anticonvulsants
  • CNR1 protein, mouse
  • Cannabinoid Receptor Agonists
  • Endocannabinoids
  • Indoles
  • Piperazines
  • Pyrrolidines
  • Receptor, Cannabinoid, CB1