Characterization of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in acute and chronic neurodegeneration models

We investigated whether soticlestat (TAK-935), a newly discovered cholesterol 24-hydroxylase (CH24H) inhibitor now in phase 3 clinical trials for Dravet and Lennox-Gastaut syndromes, has effects on neurodegeneration in both chronic and acute animal models associated with glutamate hyperexcitation. S...

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Bibliographic Details
Published in:Neuroscience research 2024-06
Main Authors: Hasegawa, Shigeo, Watanabe, Sayuri, Fujimoto, Shinji, Kondo, Shinichi, Nishi, Toshiya
Format: Article
Language:English
Subjects:
24S-hydroxycholesterol
Cholesterol 24-hydroxylase
Excitotoxicity
Glutamate
Neuroinflammation
Soticlestat
TNF-α
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Summary:We investigated whether soticlestat (TAK-935), a newly discovered cholesterol 24-hydroxylase (CH24H) inhibitor now in phase 3 clinical trials for Dravet and Lennox-Gastaut syndromes, has effects on neurodegeneration in both chronic and acute animal models associated with glutamate hyperexcitation. Soticlestat was administered at doses that approximately halve 24S-hydroxycholesterol in both experiments. In the kainic acid (KA)-induced acute hippocampal degeneration model, soticlestat ameliorated inflammatory cytokine expression, hippocampal degeneration, and memory impairment. We ruled out the possibility that soticlestat directly interferes with KA binding to the KA receptor, or that 24S-hydroxycholesterol modulates KA receptor signaling, by conducting receptor binding and cell death assays. In the PS19 chronic degeneration model of tauopathy, treatment effects were observed in neurodegeneration markers. Notably, there was a significant correlation between the levels of brain 24S-hydroxycholesterol and a proinflammatory cytokine, tumor necrosis factor-α, which is implicated in cognitive decline and lowering of seizure threshold. This is the first study demonstrating that CH24H inhibition can alleviate neurodegeneration concomitant with neuroinflammation. Herein, we discuss the interplay among 24S-hydroxycholesterol production, neuroinflammation, and excitotoxicity. Effects on neurodegeneration and neuroinflammation demonstrated in two preclinical models suggest that soticlestat is effective in ameliorating seizures and addressing cognitive dysfunction in seizure disorders. •Soticlestat ameliorated neurodegeneration both in acute and chronic setting.•Cognitive function was preserved by soticlestat treatment.•Reductions in 24S-hydroxcholesterol and TNF-α were correlated in PS19 model mice.•Soticlestat prevents hyperexcitation, neuroinflammation, and neurodegeneration.
ISSN:0168-0102
1872-8111
1872-8111
DOI:10.1016/j.neures.2024.06.005