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egl-4 modulates electroconvulsive seizure duration in C. elegans.
Invertebrate Neuroscience Pub Date : 2018-05-30 , DOI: 10.1007/s10158-018-0211-9
Monica G Risley 1, 2 , Stephanie P Kelly 1, 2 , Justin Minnerly 1, 2 , Kailiang Jia 1, 2 , Ken Dawson-Scully 1, 2
Affiliation  

Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery times. Our results suggest that PKG signaling modulates downstream K+ channel conductance to control seizure recovery time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling cascade may control seizure duration across phyla.

中文翻译:

egl-4调节秀丽隐杆线虫的电惊厥发作持续时间。

神经元兴奋性增加导致癫痫发作,并伴有虚弱的症状。有效和非侵入性的治疗方法只能缓解症状,部分原因是疾病的复杂性以及对特定分子缺陷的认识不足。癫痫治疗的一种尚未探索的新型靶标是cGMP /蛋白激酶G(PKG)途径,该途径靶向下游K +通道,该机制类似于最近获得FDA批准的抗癫痫药瑞格他滨。我们的结果表明,利用最近开发的电惊厥性癫痫发作测定,增加的PKG活性可以减少秀丽隐杆线虫的癫痫发作持续时间。苍蝇是一种完善的癫痫发作模型,秀丽隐杆线虫是一种理想的尚未开发的模型,可以轻松吸收药物并可以用于高通量筛选。在这项研究中,我们表明用钾通道开放剂,瑞格达滨或增加PKG活性的已公开药物治疗蠕虫,可显着减少癫痫发作的恢复时间。我们的研究结果表明,PKG信令调制下游ķ +通道电导在控制癫痫发作的恢复时间线虫。因此,我们提供了有力的证据,表明PKG信号级联的药理学操纵可以控制整个门系的癫痫发作持续时间。
更新日期:2018-05-30
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