Department of Psychiatry Carver College of Medicine University of Iowa Iowa City Iowa.
The Interdisciplinary Graduate Program in Molecular Medicine Carver College of Medicine University of Iowa Iowa City Iowa.
Ann Clin Transl Neurol. 2018 Dec 11;6(2):295-309. doi: 10.1002/acn3.703. eCollection 2019 Feb.
Epilepsy treatment falls short in ~30% of cases. A better understanding of epilepsy pathophysiology can guide rational drug development in this difficult to treat condition. We tested a low-cost, drug-repositioning strategy to identify candidate epilepsy drugs that are already FDA-approved and might be immediately tested in epilepsy patients who require new therapies.
Biopsies of spiking and nonspiking hippocampal brain tissue from six patients with unilateral mesial temporal lobe epilepsy were analyzed by RNA-Seq. These profiles were correlated with transcriptomes from cell lines treated with FDA-approved drugs, identifying compounds which were tested for therapeutic efficacy in a zebrafish seizure assay.
In spiking versus nonspiking biopsies, RNA-Seq identified 689 differentially expressed genes, 148 of which were previously cited in articles mentioning seizures or epilepsy. Differentially expressed genes were highly enriched for protein-protein interactions and formed three clusters with associated GO-terms including myelination, protein ubiquitination, and neuronal migration. Among the 184 compounds, a zebrafish seizure model tested the therapeutic efficacy of doxycycline, metformin, nifedipine, and pyrantel tartrate, with metformin, nifedipine, and pyrantel tartrate all showing efficacy.
This proof-of-principle analysis suggests our powerful, rapid, cost-effective approach can likely be applied to other hard-to-treat diseases.
约 30%的癫痫病例治疗效果不佳。更好地了解癫痫病理生理学可以指导针对这种治疗困难的疾病的合理药物开发。我们测试了一种低成本、药物再定位策略，以确定已获得美国食品和药物管理局 (FDA) 批准且可能立即在需要新疗法的癫痫患者中进行测试的候选癫痫药物。
对 6 名单侧内侧颞叶癫痫患者的棘波和非棘波海马脑组织活检进行了 RNA-Seq 分析。这些图谱与经 FDA 批准药物处理的细胞系的转录组相关联，鉴定出在斑马鱼惊厥试验中测试治疗效果的化合物。
在棘波与非棘波活检中，RNA-Seq 鉴定出 689 个差异表达基因，其中 148 个基因在提到惊厥或癫痫的文章中被引用。差异表达基因高度富集蛋白质-蛋白质相互作用，并形成与髓鞘形成、蛋白质泛素化和神经元迁移相关的 GO 术语的三个簇。在 184 种化合物中，一种斑马鱼惊厥模型测试了强力霉素、二甲双胍、硝苯地平、和噻嘧啶的治疗效果，二甲双胍、硝苯地平和噻嘧啶均显示出疗效。
这一原理验证分析表明，我们强大、快速、具有成本效益的方法可能适用于其他治疗困难的疾病。
