Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.
Neurobiol Dis. 2022 Oct 15;173:105835. doi: 10.1016/j.nbd.2022.105835. Epub 2022 Aug 3.
Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy.
癫痫的治疗方法主要提供癫痫发作的症状控制，因为大多数可用的药物并不针对疾病机制。此外，大约三分之一的患者无法控制癫痫发作。为了满足疾病修饰疗法的临床需求，研究应侧重于允许在最佳疗效和安全性之间进行精细平衡干预的目标。一个潜在的候选者是脑特异性酶胆固醇 24-羟化酶。这种酶将胆固醇转化为 24S-羟胆固醇，作为一种代谢物，它在调节神经元功能方面具有生物作用，这些功能与癫痫发作下的过度兴奋有关。为了研究胆固醇 24-羟化酶在癫痫发生中的作用，我们在使用临床相关剂量的获得性癫痫小鼠模型中，在疾病早期阶段给予索替司他（TAK-935/OV935），一种有效的、选择性穿透脑的该酶抑制剂。在索替司他治疗期间，与对照组相比，EEG 监测评估表明，癫痫发作的发作延迟，随后的癫痫发作次数减少了约 3 倍。值得注意的是，当癫痫发作次数减少约 4 倍，持续时间减少约 2 倍时，药物洗脱后 6.5 周仍保持治疗效果。索替司他治疗的小鼠表现出海马 CA1 神经元和齿状回苔藓细胞的神经保护作用，通过死后脑组织学评估。在癫痫发生过程中用索替司他治疗的小鼠海马神经元和神经胶质的高通量 RNA 测序表明，胆固醇 24-羟化酶的抑制作用并没有直接影响致癫痫转录网络，而是调节了一组不重叠的基因，这些基因可能对抗疾病的发病机制。在人类颞叶癫痫病灶中，我们确定胆固醇 24-羟化酶在神经元中的表达趋势较高，与癫痫小鼠相似，而在星形胶质细胞中，该酶与对照标本相比异位诱导。当在已建立的癫痫中给予索替司他时，它显著减少慢性癫痫小鼠的自发性癫痫发作次数。数据表明，胆固醇 24-羟化酶有助于自发性癫痫发作，并参与疾病进展，因此它代表了一种新型的慢性癫痫发作抑制和癫痫疾病修饰治疗靶点。
