Abstracts

Rationale: Epilepsy continues to be an area with high unmet medical need. Over 30% of patients have seizures that are poorly controlled with currently available medications, highlighting the importance of novel therapeutic approaches. TAK-935 (OV935) is a potent and specific inhibitor of cholesterol 24-hydroxylase (CH24H), a brain-specific enzyme that converts cholesterol to 24S-hydroxycholesterol (24HC). We have previously demonstrated that TAK-935 protects hippocampal neurons from kainate-induced excitotoxicity. The present study was conducted to characterize the disease-modifying potential of this novel pharmacology strategy in a murine model of mesial temporal lobe epilepsy. Methods: Mice were implanted with hippocampal and cortical electrodes for continuous EEG monitoring. One week after surgery, kainate was injected into the amygdala of awake mice to induce status epilepticus (SE). Beginning 1 h after SE onset, TAK-935 (30 mg/kg subcutaneously; n=13) or its vehicle (n=14) was administered once daily for 14 days, followed by treatment withdrawal. Spontaneous recurrent seizures (SRS) were video-EEG monitored (24/7) for 2 separate periods: 1-14 days and 2.0-2.5 months after SE. Brains were analyzed postmortem for histopathology. Satellite cohorts received TAK-935 for 1 week after SE to examine glial responses. The anti-ictogenic effects of TAK-935 were assessed in a separate paradigm, wherein mice with established SRS received TAK-935 for 2 weeks at 2 months after SE. Results: During the 14-day post-SE treatment period, TAK-935 reduced the number of seizures by half (P<0.05). Four of 13 TAK-935-treated mice did not develop SRS after treatment withdrawal, whereas all mice in the control group became epileptic. Treatment with TAK-935 significantly reduced the SRS frequency at 2.5 months after SE (seizures/day: vehicle, 3.24 +- 0.95; TAK-935, 0.96 +- 0.44;