Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Canada.
Alberta Children's Hospital Research Institute, University of Calgary, Canada; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Canada; Department of Neurosciences and Pediatrics, University of California San Diego, Rady Children's Hospital San Diego, California, USA.
Neuropharmacology. 2020 May 1;167:107988. doi: 10.1016/j.neuropharm.2020.107988. Epub 2020 Feb 4.
As one of the most common neurological disorders, epilepsy can occur throughout the lifespan and from a multiplicity of causes, including genetic mutations, inflammation, neurotrauma, or brain malformations. Although pharmacological agents are the mainstay of treatment for seizure control, an unyielding 30-40% of patients remain refractory to these medications and continue to experience spontaneous recurrent seizures with attendant life-long cognitive, behavioural, and mental health issues, as well as an increased risk for sudden unexpected death. Despite over eight decades of antiseizure drug (ASD) discovery and the approval of dozens of new medications, the percentage of this refractory population remains virtually unchanged, suggesting that drugs with new and unexpected mechanisms of action are needed. In this brief review, we discuss the need for new animal models of epilepsy, with a particular focus on the advantages and disadvantages of zebrafish. We also outline the evidence that epilepsy is characterized by derangements in mitochondrial function and introduce the rationale and promise of bioenergetics as a functional readout assay to uncover novel ASDs. We also consider limitations of a zebrafish metabolism-based drug screening approach. Our goal is to discuss the opportunities and challenges of further development of mitochondrial screening strategies for the development of novel ASDs. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
作为最常见的神经障碍之一，癫痫可以在整个生命周期中发生，其病因多种多样，包括基因突变、炎症、神经损伤或脑畸形。尽管药物治疗是控制癫痫发作的主要方法，但仍有 30-40%的患者对这些药物无反应，继续经历自发性复发性癫痫发作，伴随终身认知、行为和心理健康问题，以及突发意外死亡的风险增加。尽管抗癫痫药物（ASD）的发现已有八十多年的历史，并且批准了数十种新药，但这种难治性人群的比例实际上几乎没有变化，这表明需要具有新的、意想不到的作用机制的药物。在这篇简短的综述中，我们讨论了需要新的癫痫动物模型，特别关注斑马鱼的优缺点。我们还概述了癫痫的特征是线粒体功能紊乱的证据，并介绍了生物能量学作为一种功能性读出测定方法的原理和潜力，以发现新的 ASD。我们还考虑了基于斑马鱼代谢的药物筛选方法的局限性。我们的目标是讨论进一步开发线粒体筛选策略的机会和挑战，以开发新型 ASD。本文是题为“21 世纪的新癫痫治疗方法——从抗癫痫药物到癫痫的预防、治疗和治愈”的特刊的一部分。
