Abstracts

Rationale: Epilepsy continues to be an area with high unmet medical treatment needs with more than 30% of epilepsy patients poorly controlled on current antiepileptic therapies. Novel approaches to epilepsy treatments are needed. TAK-935 is a potent and selective inhibitor of cholesterol 24-hydroxylase (CH24H), which converts cholesterol to 24S-hydroxycholesterol (24HC), a recently identified positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors. By reducing 24HC in the brain, pharmacological inhibition of CH24H is expected to modulate glutamatergic over-activation in CNS diseases such as epilepsy. In this study, we assessed the therapeutic potential of TAK-935 in a mouse pentylenetetrazole (PTZ) model and the effect of treatment on motor coordination. Methods: PTZ (42.5 mg/kg i.p.) was given to mice twice a week to examine the effect of drug on kindling acquisition. TAK-935 was administered once daily at the dose of 30 mg/kg p.o. for the 4-week experimental period. PTZ was injected 1 h after drug treatment on testing days. For further characterization, TAK-935 was tested in the kindling model by using subcutaneous osmotic pumps at doses ranging from 0.03 to 10 mg/kg. An acute PTZ convulsion test (60 mg/kg i.p.) was conducted separately to determine whether TAK-935 can suppress PTZ-induced convulsion. The rotarod test was conducted to assess motor coordination of mice treated with TAK-935. Results: TAK-935 (30 mg/kg p.o.q.d) delayed onset of seizure development in the kindling model. Furthermore, the effects of TAK-935 on the kindling development were correlated with the pharmacodynamic response to CH24H inhibition, as assessed by the brain level of 24HC. The data suggests that an approximate 50% reduction of brain 24HC levels can produce therapeutic effects on seizure development. TAK-935 did not show notable effects on acute convulsions evoked by high-dose PTZ when 24HC was lowered by approximately 90% in the brain. Under this same treatment protocol, the rotarod performance of treated mice was also unaffected. Conclusions: These experimental results provide the first evidence to support CH24H inhibition as a novel pharmacological target for epilepsy treatment. The lack of therapeutic effects on the acute PTZ convulsion suggests that TAK-935 modulated kindling acquisition through a mechanism independent on an anti-ictogenenic potential. Funding: This study was funded by Takeda Pharmaceutical Company Limited.