Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.
STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, Department of Electrical Engineering (ESAT), KU Leuven, 3001 Leuven, Belgium.
ACS Chem Neurosci. 2020 Mar 4;11(5):730-742. doi: 10.1021/acschemneuro.9b00610. Epub 2020 Feb 21.
With the aim to discover interesting lead compounds that could be further developed into compounds active against pharmacoresistant epilepsies, we first collected 14 medicinal plants used in traditional Chinese medicine (TCM) against epilepsy. Of the six extracts that tested positive in a pentylenetetrazole (PTZ) behavioral zebrafish model, only the ethanol and acetone extracts from () also showed effective antiseizure activity in the ethylketopentenoate (EKP) zebrafish model. The EKP model is regarded as an interesting discovery platform to find mechanistically novel antiseizure drugs, as it responds poorly to a large number of marketed anti-epileptics. We then demonstrated that magnolol and honokiol, two major constituents of , displayed an effective behavioral and electrophysiological antiseizure activity in both the PTZ and the EKP models. Out of six structural analogues tested, only 4--methylhonokiol was active and to a lesser extent tetrahydromagnolol, whereas the other analogues (3,3'-dimethylbiphenyl, 2,2'-biphenol, 2-phenylphenol, and 3,3',5,5'-tetra--butyl-[1,1'-biphenyl]-2,2'-diol) were not consistently active in the aforementioned assays. Finally, magnolol was also active in the 6 Hz psychomotor mouse model, an acute therapy-resistant rodent model, thereby confirming the translation of the findings from zebrafish larvae to mice in the field of epilepsy. We also developed a fast and automated power spectral density (PSD) analysis of local field potential (LFP) recordings. The PSD results are in agreement with the visual analysis of LFP recordings using Clampfit software and manually counting the epileptiform events. Taken together, screening extracts of single plants employed in TCM, using a combination of zebrafish- and mouse-based assays, allowed us to identify allyl biphenol as a chemical scaffold for the future development of compounds with potential activity against therapy-resistant epilepsies.
为了发现可能进一步开发成针对耐药性癫痫的活性化合物的有趣先导化合物，我们首先收集了 14 种用于治疗癫痫的传统中药（TCM）的药用植物。在戊四氮（PTZ）行为斑马鱼模型中检测为阳性的六种提取物中，只有 () 的乙醇和丙酮提取物在乙基戊烯酸酯（EKP）斑马鱼模型中也显示出有效的抗惊厥活性。EKP 模型被认为是发现机制新颖的抗惊厥药物的有趣发现平台，因为它对大量市售抗癫痫药物反应不佳。然后，我们证明了厚朴酚和和厚朴酚，厚朴的两种主要成分，在 PTZ 和 EKP 模型中均显示出有效的行为和电生理抗惊厥活性。在所测试的六种结构类似物中，只有 4--甲基厚朴酚是活性的，并且程度较小的是四氢厚朴酚，而其他类似物（3,3'-二甲基联苯、2,2'-联苯酚、2-苯基苯酚和 3,3',5,5'-四--丁基-[1,1'-联苯]-2,2'-二醇）在上述测定中并不始终具有活性。最后，厚朴酚在 6 Hz 运动小鼠模型（一种急性治疗耐药的啮齿动物模型）中也具有活性，从而证实了从斑马鱼幼虫到癫痫领域小鼠的发现的转化。我们还开发了一种快速和自动的局部场电位（LFP）记录的功率谱密度（PSD）分析。PSD 结果与使用 Clampfit 软件对 LFP 记录进行的视觉分析以及手动计数癫痫样事件的结果一致。总之，使用斑马鱼和小鼠为基础的测定法筛选 TCM 中单一植物的提取物，使我们能够确定烯丙基联苯为未来开发针对治疗耐药性癫痫的潜在活性化合物的化学支架。
