Targeting firing rate neuronal homeostasis can prevent seizures

Fred Mulroe, Wei-Hsiang Lin, Connie Mackenzie-Gray Scott, Najat Aourz, Yuen Ngan Fan, Graham Coutts, R Ryley Parrish, Ilse Smolders, Andrew Trevelyan, Robert Wykes, Stuart Allan, Sally Freeman, Richard A Baines

Onderzoeksoutput: Articlepeer review

5 Citaten (Scopus)
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Samenvatting

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.

Originele taal-2English
Aantal pagina's10
TijdschriftDisease Models and Mecanisms
Volume15
Nummer van het tijdschrift10
Vroegere onlinedatum8 sep 2022
DOI's
StatusPublished - 10 okt 2022

Bibliografische nota

© 2022. Published by The Company of Biologists Ltd.

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