LAUSR

OBJECTIVE The formation of 24S-hydroxycholesterol is a brain-specific mechanism of cholesterol catabolism catalysed 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 anti-seizure medications. METHODS The anti-convulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizure, 6Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling and corneal kindling models. Soticlestat was characterized in PTZ kindling model under the steady-state pharmacokinetics to relate its anti-convulsive effects to pharmacodynamics. RESULTS Among models of acutely evoked seizures, while the 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 6Hz 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 while 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 bring 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 anti-seizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of anti-seizure medications for treatment of intractable epilepsy disorders such as development and epileptic encephalopathy.