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Targeting firing rate neuronal homeostasis can prevent seizures

Lookup NU author(s): Connie Mackenzie-Gray Scott, Ryley Parrish, Professor Andrew Trevelyan

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022. Published by The Company of Biologists Ltd. 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.

Publication metadata

Author(s): Mulroe F, Lin W-H, Mackenzie-Gray Scott C, Aourz N, Fan YN, Coutts G, Parrish RR, Smolders I, Trevelyan A, Wykes RC, Allan S, Freeman S, Baines RA

Publication type: Article

Publication status: Published

Journal: Disease Models & Mechanisms

Year: 2022

Volume: 15

Issue: 10

Online publication date: 10/10/2022

Acceptance date: 31/08/2022

Date deposited: 26/10/2022

ISSN (print): 1754-8403

ISSN (electronic): 1754-8411

Publisher: The Company of Biologists Ltd

URL: https://doi.org/10.1242/dmm.049703

DOI: 10.1242/dmm.049703

PubMed id: 36073607

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