The Atypical Anticonvulsive Mechanism of Soticlestat Characterized in Animal Models of Epilepsy
Abstract number :
3.281
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2022
Submission ID :
2204928
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Toshiya Nishi, DVM – Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan; Cameron Metcalf, PhD – Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA; Steve White, PhD – Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA
Rationale: Over 30% of all patients living with epilepsy have seizures that are poorly controlled with currently available medications, highlighting the importance of novel therapeutic mechanisms. Soticlestat is a potent and specific inhibitor of cholesterol 24-hydroxylase (CH24H), now in Phase 3 clinical trials for Dravet syndrome and Lennox-Gastaut syndrome. CH24H inhibition is a novel approach that has not been extensively studied to date. Following the initial identification of its antiepileptic potential in a mouse model of Alzheimer’s disease, the anticonvulsive properties of soticlestat were studied in rodent models of epilepsy that are commonly used to characterize antiseizure medications.
Methods: We assessed the efficacy of soticlestat in the maximal electroshock seizure, pentylenetetrazol and 6Hz psychomotor acute seizure mouse models, and the Frings audiogenic seizure-susceptible, amygdala kindling, PTZ kindling and corneal kindling mouse models of network hyperexcitability and chronic seizures.
Results: Soticlestat was effective in the audiogenic seizure and kindling acquisition models but not in the other seizure and epilepsy models. Soticlestat shortened the time of tonic-extension seizures in Fring’s audiogenic seizure-susceptible mice in a dose-dependent manner with no impact on wild running behaviours. Interestingly, soticlestat retarded amygdala kindling acquisition without altering after-discharge duration, an acknowledged measure of focal onset seizures. Soticlestat did not suppress already established kindled seizures. These findings suggest that soticlestat can attenuate seizures through a mechanism distinct from conventional antiseizure medications. We propose that soticlestat’s unique mechanism of action can modify the course of secondary seizure generalization through a reduction of brain 24S-hydroxycholesterol, which is implicated in various pathological mechanisms relevant to seizure generation in epilepsy.
Conclusions: Soticlestat constitutes a potential novel class of antiseizure medications with a unique seizure control mechanism. With its novel mechanism of action, soticlestat may be a promising therapeutic option for intractable developmental and epileptic encephalopathies such as Dravet syndrome and Lennox-Gastaut syndrome.
Funding: Takeda Pharmaceutical Company Limited
Anti-seizure Medications