Targeting firing rate neuronal homeostasis can prevent seizures.
Targeting firing rate neuronal homeostasis can prevent seizures.
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DOI：
10.1242/dmm.049703
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发表时间：
2022-10-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
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作者：
操纵放电率神经元稳态，使神经元能够调节其内在的兴奋性，提供了一个有吸引力的机会，以防止癫痫发作。然而，到目前为止，还没有基于药物的干预措施，操纵这种类型的神经元稳态机制。在这里，我们使用了果蝇和小鼠的组合，并且在后者中，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，以评估一类新的抗惊厥化合物的抗惊厥疗效，基于4-叔丁基苯甲醛（4-TBB）。作用方式包括增加放电率稳态调节剂Pumilio（PUM）的表达。在果蝇中，pum表达的敲低阻断了4-TBB的抗惊厥作用，而对小鼠大脑中经验证的PUM靶点的分析显示，暴露于该化合物后，PUM的抗惊厥作用显著降低。一项结构-活性研究鉴定了分子的活性部分，并进一步表明吡唑类似物表现出最高的功效，对PTZ诱导和电诱导的癫痫发作都有活性。这项研究提供了一个原理证明，即可以通过调节放电率神经元稳态来实现抗惊厥作用，并确定了一种可能用于未来开发的化合物。 癫痫仍然具有挑战性的治疗。在这项研究中，我们表明，操纵内源性机制，保持稳定的神经元活动是一种可能的途径，以更好地管理这种疾病。
Manipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, to date, no drug-based interventions have been reported that manipulate this type of neuronal homeostatic mechanism. Here, we used a combination of Drosophila and mouse, and, in the latter, both a pentylenetetrazole (PTZ)-induced seizure model and an electrically induced seizure model for refractory seizures to evaluate the anticonvulsant efficacy of a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB). The mode of action included increased expression of the firing rate homeostatic regulator Pumilio (PUM). Knockdown of pum expression, in Drosophila, blocked anticonvulsive effects of 4-TBB, while analysis of validated PUM targets in mouse brain revealed significant reductions following exposure to this compound. A structure-activity study identified the active parts of the molecule and, further, showed that the pyrazole analogue demonstrates highest efficacy, being active against both PTZ-induced and electrically induced seizures. This study provides a proof of principle that anticonvulsant effects can be achieved through regulation of firing rate neuronal homeostasis and identifies a possible chemical compound for future development. Epilepsy remains challenging to treat. In this study, we show that manipulating endogenous mechanisms that maintain stability of neuronal activity represents a possible route to better manage this disorder.
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影响因子：
4.3
作者：
Follwaczny P;Schieweck R;Riedemann T;Demleitner A;Straub T;Klemm AH;Bilban M;Sutor B;Popper B;Kiebler MA
通讯作者：
Kiebler MA
影响因子：
4.3
作者：
Lin WH;Giachello CN;Baines RA
通讯作者：
Baines RA
影响因子：
16.2
作者：
Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM
影响因子：
6.1
作者：
Berdichevsky, Yevgeny;Dzhala, Volodymyr;Mail, Michelle;Staley, Kevin J.
通讯作者：
Staley, Kevin J.
DOI：
10.1016/b978-0-12-804066-9.00024-9
发表时间：
2017-01-01
期刊：
MODELS OF SEIZURES AND EPILEPSY, 2ND EDITION
影响因子：
--
作者：
Baines, Richard A.;Giachello, Carlo N. G.;Lin, Wei-Hsiang
通讯作者：
Lin, Wei-Hsiang