Banerji Rajeswari, Huynh Christopher, Figueroa Francisco, Dinday Matthew T, Baraban Scott C, Patel Manisha
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, CA 80045, USA.
Department of Neurological Surgery, Epilepsy Research Laboratory, University of California, San Francisco, CA 94143, USA.
Brain Commun. 2021 Jan 25;3(1):fcab004. doi: 10.1093/braincomms/fcab004. eCollection 2021.
Energy-producing pathways are novel therapeutic targets for the treatment of neurodevelopmental disorders. Here, we focussed on correcting metabolic defects in a catastrophic paediatric epilepsy, Dravet syndrome which is caused by mutations in sodium channel NaV1.1 gene, . We utilized a translatable zebrafish model of Dravet syndrome () which exhibits key characteristics of patients with Dravet syndrome and shows metabolic deficits accompanied by down-regulation of gluconeogenesis genes, and . Using a metabolism-based small library screen, we identified compounds that increased gluconeogenesis via up-regulation of gene expression in larvae. Treatment with PK11195, a activator and a translocator protein ligand, normalized dys-regulated glucose levels, metabolic deficits, translocator protein expression and significantly decreased electrographic seizures in mutant larvae. Inhibition of in wild-type larvae mimicked metabolic and behaviour defects observed in mutants. Together, this suggests that correcting dys-regulated metabolic pathways can be therapeutic in neurodevelopmental disorders such as Dravet syndrome arising from ion channel dysfunction.
能量产生途径是治疗神经发育障碍的新型治疗靶点。在此，我们专注于纠正一种严重的儿童癫痫——德雷维特综合征中的代谢缺陷，该综合征由钠通道NaV1.1基因突变引起。我们利用了一种可转化的德雷维特综合征斑马鱼模型，该模型表现出德雷维特综合征患者的关键特征，并显示出代谢缺陷，同时伴随着糖异生基因PCK1和G6PC的下调。通过基于代谢的小型文库筛选，我们在scn1lab突变幼虫中鉴定出了通过上调PCK1基因表达来增加糖异生的化合物。用PK11195（一种TSPO激活剂和转位蛋白配体）进行治疗，可使突变幼虫中失调的葡萄糖水平、代谢缺陷、转位蛋白表达正常化，并显著减少脑电图癫痫发作。在野生型幼虫中抑制TSPO会模拟scn1lab突变体中观察到的代谢和行为缺陷。总之，这表明纠正失调的代谢途径对神经发育障碍如由离子通道功能障碍引起的德雷维特综合征具有治疗作用。
