Epilepsy is one of the most common serious neurological conditions, affecting 1 in 131 people in the UK. Patients with epilepsy suffer recurrent spontaneous seizures when neuronal activity elevates beyond physiological limits. Although current anti-epileptic drugs can effectively prevent seizures in some patients, up to 20% of paediatric and 40% of adult patients are refractory to treatment. One therapeutic avenue that has not yet been pursued for epilepsy is targeting neuronal homeostasis. PUMILIO (PUM) is a transcriptional repressor that maintains neuron action potentials within physiological limits and, importantly, is abnormally reduced in patients with epilepsy. In their recent article, Richard Baines and colleagues, therefore, investigated PUM as a therapeutic target for epilepsy.

The authors identified a new compound, 4-tert-butyl-benzaldehyde (4-TBB), which could increase expression and stability of PUM in Drosophila and mice, and had physiochemical properties compatible with clinical use. They pre-treated diverse Drosophila and mouse models of epilepsy with 4-TBB prior to electrical or chemical induction of seizures. The team found that 4-TBB acts as an anticonvulsant, significantly reducing behavioural and physiological signs of seizure. The authors also confirmed that 4-TBB acts – at least in part – through modulation of PUM, as protein levels of downstream targets of PUM were reduced in treated mouse brains and because RNAi-induced reduction of PUM significantly diminished the anticonvulsant activity of 4-TBB in Drosophila.

The authors then identified RAB216, a more-potent analogue of 4-TBB, which also increased PUM expression, and induced anticonvulsant activity in Drosophila and mice, at significantly lower concentrations than 4-TBB. Moreover, RAB216 also reduced the duration of seizures in an electrically induced seizure assay within a murine model that recapitulates drug-refractory epilepsy.

The Baines lab identified two anticonvulsant compounds that modulate PUM expression and activity to oppose the high neuronal activity associated with seizures. This approach modulates neuronal homeostasis, which may incur fewer side effects, as these mechanisms are tightly controlled to avoid under- or over-activation. Interestingly, although mice were pre-treated with 4-TBB for 3 days prior to seizure induction, there were no overt signs of side effects. However, future work is required to investigate the full mode of action of the new compounds, beyond the modulation of PUM activity. Moreover, as PUM is expressed systemically, the development of compounds targeting central nervous system-specific downstream targets or co-factors of PUM could further minimise potential side effects. Nevertheless, the authors have demonstrated the potential of a novel approach to treating epilepsy, which may reduce the proportion of drug-refractory patients.

The image shows the dorsal hippocampus of a mouse with viral vector-mediated overexpression of Pum1 stained in green and DAPI staining in blue. For permission to reuse, contact Robert Wykes at [email protected]

DMM Research or Resource articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.

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Dis. Model. Mech.
15
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dmm049703
. doi:10.1242/dmm.049703
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.