The nav1.1 Potentiator, A1362WM, Increases Excitability of Putative Fast Spiking Interneurons Ex-vivo, but Fails to Block Febrile Seizures in Dravet Mouse Model
Abstract number :
1.282
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2022
Submission ID :
2205043
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Jesper Bastlund, PhD – H. Lundbeck A/S; tau benned-Jensen, PhD – H. Lundbeck A/S; Christoffer bundgaard, PhD – H. Lundbeck A/S; benjamin Hall, PhD – H. Lundbeck A/S; charlotte Hougaard, PhD – H. Lundbeck A/S; julie klint, PhD – H. Lundbeck A/S; Bettina Laursen, PhD – H. Lundbeck A/S; Lars Rasmussen, PhD – H. Lundbeck A/S
Rationale: The voltage-gated Nav1.1 channels are mainly expressed by fast spiking interneurons (FSI) e.g. the parvalbumin positive interneuron subtype, where they control FSI excitability by governing the upstroke of the action potential. Loss-of-function mutations in Nav1.1 channels lead to seizure disorders and in its most severe form Dravet syndrome. Thus, pharmacological potentiation of Nav1.1 channels holds promise as a therapeutic strategy for Dravet syndrome and many other brain disorders.
Methods: In the present study, we have characterized the pharmacological profile of the novel selective Nav1.1 potentiator A1362WM, using both recombinantly expressed Nav1.x channels and automated electrophysiology, slice electrophysiology and in-vivo assays for febrile seizures associated with Dravet syndrome.
Results: Using recombinantly expressed Nav1.x channels, A1362WM was confirmed to be a selective potentiator of Nav1.1 channels toward other major Nav1.x subtypes expressed in the adult mouse brain. Using patch clamp of putative fast spiking interneurons in hippocampal slices, an increase in excitability by bath perfusion of A1362WM was demonstrated. Next, we tested 30, 100, and 300 mg/kg of A1362WM in a preclinical mouse model of hyperthermia-induced seizures in Dravet syndrome and compared to the reference antiepileptic drug valproate. Valproate significantly reduced latency to hyperthermia-induced tonic seizures, whereas A1362WM did not significantly affect the latency to seizure.
Conclusions: In summary, A1362WM is a potent potentiator of voltage-gated Nav1.1 channels demonstrating capacity to increase excitability of putative fast spiking interneurons. A1362WM at doses up to 300 mg/kg did not affect febrile seizure expression in a mouse model for Dravet syndrome.
Funding: H. Lundbeck A/S
Anti-seizure Medications