Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy.
Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy.
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DOI：
10.1016/j.neuroscience.2013.11.040
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发表时间：
2014-02-14
期刊：
影响因子：
3.3
通讯作者：
Chan, S. S. L.
中科院分区：
文献类型：
--
作者：
Rahn, J. J.;Bestman, J. E.;Josey, B. J.;Inks, E. S.;Stackley, K. D.;Rogers, C. E.;Chou, C. J.;Chan, S. S. L.
癫痫是一种使人衰弱的疾病，影响着世界上 1-2% 的人口。尽管患病率很高，但 30% 的癫痫患者无法通过当前药物成功控制，这表明迫切需要新型抗癫痫药物 (AED)。为了寻找治疗癫痫的新疗法，我们首先使用成熟的幼虫斑马鱼模型筛选抑制 HDAC 的药物，这些药物与目前使用的一些 AED 一样。在该模型中，受精后 7 天 (dpf) 幼虫用广泛使用的癫痫诱导化合物戊四氮 (PTZ) 进行治疗，该化合物会刺激游泳行为的快速增加，而游泳行为此前被确定为癫痫发作的可测量表现。在我们的第一次筛选中，我们测试了多种不同的 HDAC 抑制剂，发现其中一种 NQN1 可以显着降低游泳活动至与 VPA 相同的水平。我们继续筛选结构相关的化合物，包括维生素 K3 (VK3) 和许多新型维生素 K (VK) 类似物。我们发现，VK3 是 PTZ 诱导的游泳活动的强效抑制剂，我们的几种新型化合物也是如此。随后，国家神经疾病和中风研究所 (NINDS) 抗惊厥筛选项目对其中三种化合物在小鼠癫痫模型上进行了测试。化合物 2h 在最小阵挛性癫痫发作 (6 Hz) 和角膜点燃小鼠癫痫模型中尤其能有效减少癫痫发作，且没有可观察到的毒性。由于 VK3 影响线粒体功能，我们测试了我们的化合物对小鼠海马细胞系线粒体呼吸和 ATP 产生的影响。我们证明这些化合物影响 ATP 代谢并增加细胞 ATP 总量。我们的数据表明这些和其他 VK 类似物在预防癫痫发作方面的潜在效用，并表明这种保护的潜在机制可能在于这些化合物影响能量产生的能力。
Epilepsy is a debilitating disease affecting 1-2% of the world’s population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a critical need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit HDACs using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compound pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously determined to be a measurable manifestation of seizures. In our first screen, we tested a number of different HDAC inhibitors and found that one, NQN1, significantly decreased swim activity to levels equal to that of VPA. We continued to screen structurally related compounds including Vitamin K3 (VK3) and a number of novel Vitamin K (VK) analogues. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compounds. Three of these compounds were subsequently tested on mouse seizure models at the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compound 2h reduced seizures particularly well in the minimal clonic seizure (6 Hz) and corneal kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compounds on mitochondrial respiration and ATP production in a mouse hippocampal cell line. We demonstrate that these compounds affect ATP metabolism and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogues for prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compounds to affect energy production.
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影响因子：
4.2
作者：
Fass, Daniel M.;Shah, Rishita;Ghosh, Balaram;Hennig, Krista;Norton, Stephanie;Zhao, Wen-Ning;Reis, Surya A.;Klein, Peter S.;Mazitschek, Ralph;Maglathlin, Rebecca L.;Lewis, Timothy A.;Haggarty, Stephen J.
通讯作者：
Haggarty, Stephen J.
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
3.1
作者：
Alsdorf, Rachel;Wyszynski, Diego F
通讯作者：
Wyszynski, Diego F
影响因子：
2.2
作者：
Barton, ME;Klein, BD;White, HS
通讯作者：
White, HS
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF