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

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.

• Authors: Lyndsey L Anderson, Peter T Doohan, Nicole A Hawkins, Dilara Bahceci, Sumanta Garai, Ganesh A Thakur, Jennifer A Kearney, Jonathon C Arnold
• Journal: Neuropharmacology (Neuropharmacology) Vol. 205 Pg. 108897 (03 01 2022) ISSN: 1873-7064 [Electronic] England
• PMID: 34822817 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• 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

Topics

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