Serotonin receptors in epilepsy: Novel treatment targets?

Sourbron, Jo; Lagae, Lieven

doi:10.1002/epi4.12580

Cited by 32 publications

(23 citation statements)

References 166 publications

(368 reference statements)

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“…Fenfluramine targets the serotonin [5-hydroxytryptamine (5-HT)] system and sigma-1 receptors. 37,[71][72][73][74][75] Fenfluramine and its active metabolite, norfenfluramine, are 5-HT-releasing agents that disrupt vesicular storage of serotonin in presynaptic nerve terminals and also reduce the reuptake of serotonin from the synaptic cleft by inhibition of serotonin transporter proteins. 71 The consequent elevation in synaptic concentrations of serotonin is anticipated to result in the activation of multiple 5-HT receptor subtypes.…”

Section: Use Of Asms In the Treatment Of Deesmentioning

confidence: 99%

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

Sills

2023

Ther Adv Neurol Disord

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Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox–Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.

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Section: Use Of Asms In the Treatment Of Deesmentioning

confidence: 99%

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

Sills

2023

Ther Adv Neurol Disord

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“…Aside from the indirect effect of increasing extracellular 5-HT levels, FFA’s metabolites, D- and L-norfenfluramine (norFFA), activate 5-HT receptors directly [ 16 , 17 ]. 5-HT receptors are present in the neocortex and hippocampus.…”

Section: The Mechanisms Of the Antiseizure Effect Of Fenfluraminementioning

confidence: 99%

Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy

Samanta

2022

Children

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Despite the availability of more than 30 antiseizure medications (ASMs), the proportion of patients who remain refractory to ASMs remains static. Refractory seizures are almost universal in patients with epileptic encephalopathies. Since many of these patients are not candidates for curative surgery, there is always a need for newer ASMs with better efficacy and safety profile. Recently, the anti-obesity medication fenfluramine (FFA) has been successfully repurposed, and various regulatory agencies approved it for seizures associated with Dravet and Lennox–Gastaut syndromes. However, there is a limited in-depth critical review of FFA to facilitate its optimal use in a clinical context. This narrative review discusses and summarizes the antiseizure mechanism of action of FFA, clinical pharmacology, and clinical studies related to epilepsy, focusing on efficacy and adverse effects.

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“…Thus, a shift in the balance of dopamine receptors toward an increase in D1 receptors leads to increased neuronal excitability, which has been observed in epileptic patients and model animals [ 62 , 63 , 64 ]. In addition to the glutamatergic and dopaminergic systems, the other neurotransmitter systems were also shown to be affected in epileptogenesis development [ 65 , 66 , 67 , 68 , 69 , 70 , 71 ].…”

Section: Pathophysiological Mechanisms Of Epilepsymentioning

confidence: 99%

Rodent Models of Audiogenic Epilepsy: Genetic Aspects, Advantages, Current Problems and Perspectives

et al. 2022

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Animal models of epilepsy are of great importance in epileptology. They are used to study the mechanisms of epileptogenesis, and search for new genes and regulatory pathways involved in the development of epilepsy as well as screening new antiepileptic drugs. Today, many methods of modeling epilepsy in animals are used, including electroconvulsive, pharmacological in intact animals, and genetic, with the predisposition for spontaneous or refractory epileptic seizures. Due to the simplicity of manipulation and universality, genetic models of audiogenic epilepsy in rodents stand out among this diversity. We tried to combine data on the genetics of audiogenic epilepsy in rodents, the relevance of various models of audiogenic epilepsy to certain epileptic syndromes in humans, and the advantages of using of rodent strains predisposed to audiogenic epilepsy in current epileptology.

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Serotonin receptors in epilepsy: Novel treatment targets?

Cited by 32 publications

References 166 publications

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy

Rodent Models of Audiogenic Epilepsy: Genetic Aspects, Advantages, Current Problems and Perspectives

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