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, Rob Wykes, Stuart Allan, Sally Freeman, Richard Baines

Research output: Contribution to journalArticlepeer-review


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 use 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 anticonvulsant efficacy of a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB). The mode-of-action includes increased expression of the firing rate homeostatic regulator PUMILIO (PUM). Knock-down of PUM expression, in Drosophila, blocks anticonvulsive effects of 4-TBB, whilst analysis of validated PUM targets in mouse brain show significant reductions following exposure to this compound. A structure-activity study identifies the active parts of the molecule and, further, shows the pyrazole analogue demonstrates highest efficacy, being active against both PTZ-, 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.
Original languageEnglish
JournalDMM Disease Models and Mechanisms
Issue number10
Publication statusPublished - 1 Oct 2022


  • Animals
  • Anticonvulsants/pharmacology
  • Benzaldehydes/adverse effects
  • Drosophila
  • Homeostasis
  • Mice
  • Neurons
  • Pentylenetetrazole/adverse effects
  • Pyrazoles/therapeutic use
  • Seizures/drug therapy


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