University of Washington, Department of Pharmacy, Seattle, WA, USA.
Research, Takeda Pharmaceutical Company Limited, Fujisawa, 251-8555, Japan; Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
Neuropharmacology. 2023 Jan 1;222:109310. doi: 10.1016/j.neuropharm.2022.109310. Epub 2022 Oct 29.
Temporal lobe epilepsy is the most common form of acquired epilepsy and can arise due to multiple inciting events, including central nervous system (CNS) infection. CNS infection with the Theiler's murine encephalomyelitis virus (TMEV) in male C57Bl/6J mice leads to acute, drug-resistant handling-induced seizures. 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 novel CH24H inhibitor, soticlestat (SOT; or TAK-935), demonstrates the potential to restore excitatory/inhibitory balance in multiple preclinical models of hyperexcitability. This study thus sought to characterize the anticonvulsant potential of SOT in the TMEV model. Treatment with SOT (30 mg/kg, p.o.; n = 30) 0-7 days post-infection (DPI) reduced overall seizure burden and severity. SOT administration significantly delayed onset of infection-induced Racine stage 5 seizures, from 8.6 ± 0.6 (VEH-treated) to 10.8 ± 0.8 (SOT-treated) observation sessions. Infected mice were then allowed 36 days treatment-free recovery before assessing impact of earlier drug administration on epilepsy-related cognitive and behavioral comorbidities, including a non-habituated open field (OF) task. Total OF distance traveled was significantly less in SOT-treated mice compared to VEH-treated mice, suggesting attenuated TMEV-induced spatial memory deficits, or reduced chronic hyperexcitability. Mice with history of SOT treatment also spent significantly more time and traveled farther in the OF center, indicative of reduced epilepsy-induced anxiety-like behavior. These studies suggest that SOT is a mechanistically novel agent for symptomatic seizure control. Moreover, acute SOT administration during an epileptogenic insult may attenuate the resulting long-term behavioral comorbidities of epilepsy.
颞叶癫痫是最常见的获得性癫痫，可由多种激发事件引起，包括中枢神经系统 (CNS) 感染。雄性 C57Bl/6J 小鼠中枢神经系统感染 Theiler's 鼠脑脊髓炎病毒 (TMEV) 会导致急性、耐药性处理诱导的癫痫发作。胆固醇 24-羟化酶 (CH24H) 是一种脑特异性酶，可将胆固醇转化为 24S-羟胆固醇；这是大脑中胆固醇分解代谢的主要机制。新型 CH24H 抑制剂 soticlestat (SOT；或 TAK-935) 在多种超兴奋性的临床前模型中显示出恢复兴奋性/抑制性平衡的潜力。因此，本研究旨在研究 SOT 在 TMEV 模型中的抗惊厥潜力。在感染后 0-7 天 (DPI) 时，SOT（30mg/kg，口服；n=30）治疗可降低总癫痫发作负担和严重程度。SOT 给药显著延迟了感染诱导的 Racine 5 期癫痫发作的发作，从 VEH 治疗的 8.6±0.6 观察期延迟至 SOT 治疗的 10.8±0.8 观察期。然后，在评估早期药物治疗对癫痫相关认知和行为合并症的影响之前，让感染的小鼠进行 36 天的无治疗恢复期，包括非习惯性开放场 (OF) 任务。与 VEH 治疗的小鼠相比，SOT 治疗的小鼠在 OF 中总行驶距离明显减少，表明 TMEV 诱导的空间记忆缺陷或慢性超兴奋性降低。有 SOT 治疗史的小鼠在 OF 中心停留的时间和行驶的距离也明显更长，表明癫痫引起的焦虑样行为减少。这些研究表明，SOT 是一种治疗症状性癫痫发作的新型机制药物。此外，在癫痫发作性损伤期间给予急性 SOT 治疗可能会减轻由此产生的癫痫长期行为合并症。
