Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Abstract

Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.

Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications

“…Furthermore, experiments with purified recombinant human CYP46A1 and subsequent 24HC quantifications by isotope-dilution gas chromatography-mass spectrometry, a highly accurate method, did not confirm tight soticlestat binding to P450 as indicated by a high K i value of 7.3 μM ( Chen et al, 2020 ). This is in contrast to the reported 4.5 nM IC 50 determined in cultured cells transfected with CYP46A1 using 24HC detection by thin layer chromatography ( Nishi et al, 2020 ). Apparently, additional soticlestat characterizations are needed to ascertain its binding specificity for CYP46A1.…”

“…The 11 C-labeled form of soticlestat was synthesized for use in positron emission topography ( Chen et al, 2020 ). Yet, the drug characterization in this study yielded different results when compared to those of the developers of this compound ( Nishi et al, 2020 ). 11 C-soticlestat was found to have low uptake by the brain and a marginal CYP46A1 specificity ( Chen et al, 2020 ).…”

“…In a different investigation, a novel CYP46A1 inhibitor called soticlestat (also known as TAK-935 and OV935) was administered to the AD model of amyloidogenesis (APP/PS1-Tg mice) and evaluated for pharmacokinetics, pharmacodynamics, and functional effects. In only 8 h (the first measured time point), soticlestat inhibited CYP46A1 after a single oral dose of 10 mg/kg of body weight, whereas the three daily administrations reduced the brain 24HC levels to a steady state ( Nishi et al, 2020 ). An 8-week treatment of young APP/PS1-Tg mice with soticlestat (10 mg/kg of body weight) starting at the age of 7 weeks increased animal survival from 16 to 28 in the groups of 30 animals.…”

“…A 2-week treatment of APP/PS1-Tg mice with the same dose of soticlestat followed by a 100 mM KCl hippocampal perfusion to induce the hyperexcitability phenotype suppressed the elevation of extracellular Glu and reduced seizure-like behaviors. In another experiment, a 2-week treatment of 3-month old APP/PS1-Tg mice did not alter the hippocampal levels of the Aβ42 peptide and did not have notable effects on motor coordination or spontaneous locomotor activity ( Nishi et al, 2020 ). Besides APP/PS1-Tg mice, soticlestat was assessed on mouse models of epilepsy ( SCN1A mice and pentylenetetrazol-induced kindling) and was shown to decrease seizure burden in the former but not the latter ( Bialer et al, 2018 ), although full papers describing these findings remain to be published.…”

Brain-Specific Oxysterols and Risk of Schizophrenia in Clinical High-Risk Subjects and Patients With Schizophrenia

“…These data implied that lowering 24OHC levels might be a therapeutic way in schizophrenia treatment. Inhibition of CYP46A1 has therapeutic relevance to CNS hyperexcitability supported the therapeutic way of lowering 24OHC to schizophrenia ( 54 ). Hence, the role of 24OHC is still somewhat puzzling, but a recent report shed a new light that esterification of 24OHC is a prerequisite for inducing cell death ( 55 ).…”