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Review
. 2022 Jun;7(2):231-246.
doi: 10.1002/epi4.12580. Epub 2022 Feb 2.

Serotonin receptors in epilepsy: Novel treatment targets?

Jo Sourbron  1   2 , Lieven Lagae  1
Affiliations
Review

Serotonin receptors in epilepsy: Novel treatment targets?

Jo Sourbron et al. Epilepsia Open. 2022 Jun.

Abstract

Despite the availability of over 30 antiseizure medications (ASMs), there is no "one size fits it all," so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5-hydroxytryptamine, 5-HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only a few ASM, such as fenfluramine (FA), act via 5-HT. There are 14 different 5-HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5-HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each "5-HT subtype" separately and its relation to "epilepsy or seizures." Most research underlines the antiseizure activity of 5-HT1A,1D,2A,2C,3 agonism and 5-HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5-HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment.

Keywords: 5-HT; SUDEP; antiseizure medication; epilepsy treatment; fenfluramine.

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Conflict of interest statement

LL received grants, and is a consultant and/or speaker for Zogenix; LivaNova, UCB, Shire, Eisai, Novartis, Takeda/Ovid, NEL, Epihunter. LL has a patent for ZX008 (fenfluramine) for the treatment of Dravet syndrome and infantile epilepsies assigned to his institution and licensed to Zogenix. The remaining author (JS) has no conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
Fourteen serotonin (5‐HT) receptor subtypes. Stimulation (+) of several receptor subtypes (5‐HT1A,1D,2A,2C,3) and inhibition (−) of the 5‐HT6 subtype have been implicated in antiseizure activity (row literature). For the 5‐HT2B,4,7 subtypes data are contradictory, depicted in white. 5‐HT1D,2A,2C subtypes are likely involved in the mechanism of fenfluramine (zebrafish (ZF) data). 5‐HT2A,2C,4,7 subtypes are likely involved in the mechanism of fenfluramine (mice data). See text for the references of these preclinical studies
FIGURE 2
FIGURE 2
Serotonergic mechanisms of action of fenfluramine: (1) increase of GABAergic dendritic arborization via 5‐HT and GABAergic activity; (2) decrease of serotonin reuptake by inhibition of SERT; (3) increase of fusion and release of synaptic vesicles; (4) the two previous modulatory lead to an increase of 5‐HT in the synaptic cleft and thereby stimulation of 5‐HT receptor subtypes; and (5) fenfluramine directly stimulates at least five serotonin (5‐HT) receptor subtypes (5‐HT1D,2A,2C,4,7) (zebrafish and mice data),, thereby increasing gamma‐aminobutyric acid inhibitory input and decreasing glutaminergic excitatory output. Regarding the sigma receptor modulation, we refer to Martin et al 2020. 5‐HT = serotonin; GABA = gamma aminobutyric acid; GLUT = glutamine; SERT = serotonin transporter
See this image and copyright information in PMC

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