1. Targeting firing rate neuronal homeostasis can prevent seizures.
- Author
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Mulroe F, Lin WH, Mackenzie-Gray Scott C, Aourz N, Fan YN, Coutts G, Parrish RR, Smolders I, Trevelyan A, Wykes RC, Allan S, Freeman S, and Baines RA
- Subjects
- Animals, Benzaldehydes adverse effects, Drosophila, Homeostasis, Mice, Neurons, Pyrazoles therapeutic use, Seizures drug therapy, Seizures prevention & control, Anticonvulsants pharmacology, Anticonvulsants therapeutic use, Pentylenetetrazole adverse effects
- Abstract
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., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)
- Published
- 2022
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