Anticonvulsive properties of soticlestat, a novel cholesterol 24-hydroxylase inhibitor.
CYP46A1
anticonvulsants
cholesterol 24-hydroxylase
epilepsy
soticlestat
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
revised:
10
03
2022
received:
23
12
2021
accepted:
18
03
2022
pubmed:
23
3
2022
medline:
7
6
2022
entrez:
22
3
2022
Statut:
ppublish
Résumé
The 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. The 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. Among 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. 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.
Identifiants
pubmed: 35316533
doi: 10.1111/epi.17232
pmc: PMC9311151
doi:
Substances chimiques
Anticonvulsants
0
Piperidines
0
Pyridines
0
soticlestat
1766MU795L
Cholesterol 24-Hydroxylase
EC 1.14.14.25
Pentylenetetrazole
WM5Z385K7T
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1580-1590Informations de copyright
© 2022 Takeda Pharmaceutical Company Limited. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
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