ArticleEpilepsia2022
Anticonvulsive properties of soticlestat, a novel cholesterol 24-hydroxylase inhibitor.
Article in Epilepsia, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Clinical Failure Validates a Fifth Predictive Preclinical Antiseizure Medicine Discovery Model.Epilepsy currents · 2026Article
- Structure-Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors.Molecules (Basel, Switzerland) · 2026Article
- Recent Advances in the Management of Seizures in Children.Paediatric drugs · 2026Review
- Oxysterol signaling in the central nervous system: cellular mechanisms and implications for neurodegeneration.Frontiers in molecular neuroscience · 2026Review
- Frequency-Dependent Mechanism of 24-Hydroxycholesterol-Mediated Modulation of Neurotransmitter Release at the Mouse Neuromuscular Junction: The Role of Reactive Oxygen Species.Neurochemical research · 2025Article
- A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat.Epilepsia · 2025Review
- Antiseizure Medications: Advancements, Challenges, and Prospects in Drug Development.Current neuropharmacology · 2025Review
- Role of cholesterol in modulating brain hyperexcitability.Epilepsia · 2025Review
- Efficacy, safety, and tolerability of soticlestat (TAK-935) as adjunctive therapy in pediatric patients with dravet syndrome and Lennox-Gastaut syndrome: a meta-analysis of 3 randomized controlled trials.Frontiers in pharmacology · 2025Review
- The bidirectional role of music effect in epilepsy: Friend or foe?Epilepsia open · 2024Review
- New epilepsy therapies in development.Nature reviews. Drug discovery · 2024Review
- Innovative drug discovery strategies in epilepsy: integrating next-generation syndrome-specific mouse models to address pharmacoresistance and epileptogenesis.Expert opinion on drug discovery · 2024Review
- Phase 1 pharmacokinetic and safety study of soticlestat in participants with mild or moderate hepatic impairment or normal hepatic function.Pharmacology research & perspectives · 2024Article
- 7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite.International journal of molecular sciences · 2024Article
- Oxysterols in Central and Peripheral Synaptic Communication.Advances in experimental medicine and biology · 2024Article
- Population pharmacokinetics, enzyme occupancy, and 24S-hydroxycholesterol modeling of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in healthy adults.Clinical and translational science · 2023Article
- Cannabidiol reveals a disruptive strategy for 21st century epilepsy drug discovery.Experimental neurology · 2023Review
- Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies.Therapeutic advances in neurological disorders · 2023Review
- Rodent Models of Audiogenic Epilepsy: Genetic Aspects, Advantages, Current Problems and Perspectives.Biomedicines · 2022Review
- Anticonvulsive properties of soticlestat, a novel cholesterol 24-hydroxylase inhibitor.Epilepsia · 2022Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveThe formation of 24S-hydroxycholesterol is a brain-specific mechanism of cholesterol catabolism catalyzed by cholesterol 24-hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S-hydroxycholesterol has not been fully studied. Soticlestat is a novel small-molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.
methodsThe anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6-Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady-state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.
resultsAmong models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6-Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S-hydroxycholesterol lowering in the brain, suggesting that 24S-hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition. SIGNIFICANCE: The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.
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