Targeting neuronal homeostasis to prevent seizures-猫眼课题宝

DOI：

10.1101/2022.03.07.483229

发表时间：

2022-03

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Fred Mulroe;Wei-Hsiang Lin;Connie Mackenzie-Gray Scott;Najat Aourz;Yuen Ngan Fan;Graham A. Coutts;R. R. Parrish-R.;I. Smolders;A. Trevelyan;Robert Wykes;S. Allan;Sally Freeman;R. Baines

操纵神经元稳态，使神经元能够调节其内在兴奋性，提供了一个有吸引力的机会，以防止癫痫发作。然而，还没有报道直接操纵神经元稳态的抗惊厥化合物。在这里，我们描述了一类新的抗惊厥化合物，基于4-叔丁基-苯甲醛（4-TBB），与模式的行动，包括增加表达的稳态调节Pumilio（Pum）。在果蝇和小鼠中，我们使用戊四唑（PTZ）诱导的癫痫发作模型和电诱导的癫痫发作模型用于难治性癫痫发作，以评估抗惊厥疗效。吡唑类似物（RAB 216）表现出最佳疗效，保护50%的小鼠免受PTZ诱导的癫痫发作。在果蝇中，Pum的敲低阻断了抗惊厥作用，而对经验证的Pum靶点的分析显示，小鼠大脑暴露于4-TBB后，Pum显著降低。这项研究提供了通过调节神经元稳态可以实现抗惊厥作用的原理证明，并确定了未来开发的化学先导化合物。

Manipulating neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, no anticonvulsant compounds have yet been reported that directly manipulate neuronal homeostasis. Here, we describe a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB), with a mode-of-action that includes increased expression of the homeostatic regulator Pumilio (Pum). In Drosophila and mouse we use a pentylenetetrazole (PTZ) induced seizure model, and an electrically induced seizure model for refractory seizures to evaluate anticonvulsant efficacy. The pyrazole analogue (RAB216) demonstrates best efficacy, protecting 50% of mice from PTZ-induced seizure. Knock-down of Pum, in Drosophila, blocks anticonvulsive effects, whilst analysis of validated Pum targets show significant reductions following exposure of mouse brain to 4-TBB. This study provides proof-of-principle that anticonvulsant effects can be achieved through regulation of neuronal homeostasis and identifies a chemical lead compound for future development.

Targeting neuronal homeostasis to prevent seizures

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