lorcaserin and Seizures

Adjunctive fenfluramine hydrochloride, classically described as acting pharmacologically through a serotonergic mechanism, has demonstrated a unique and robust clinical response profile with regard to its magnitude, consistency, and durability of effect on seizure activity in patients with pharmacoresistant Dravet syndrome. Recent findings also support long-term improvements in executive functions (behavior, emotion, cognition) in these patients. The observed clinical profile is inconsistent with serotonergic activity alone, as other serotonergic medications have not been demonstrated to have these clinical effects. This study investigated a potential role for σ. Radioligand binding assays tested the affinity of fenfluramine for 47 receptors associated with seizures in the literature, including σ receptors. Cellular function assays tested fenfluramine and norfenfluramine (its major metabolite) activity at various receptors, including adrenergic, muscarinic, and serotonergic receptors. The σ. Fenfluramine and norfenfluramine bound ≥30% to β. Fenfluramine demonstrated modulatory activity at σ

Topics: Animals; Benzazepines; CHO Cells; Cricetinae; Cricetulus; Fenfluramine; HEK293 Cells; Humans; Male; Mice; Morpholines; Protein Binding; Radioligand Assay; Rats; Receptors, sigma; Seizures; Sigma-1 Receptor

Topics: Animals; Benzazepines; Disease Models, Animal; Ethylamines; Fenfluramine; Indoles; Mice; Piperazines; Pyrazines; Rats; Receptor, Serotonin, 5-HT2C; Seizures; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome

Dravet syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics. We demonstrate that clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways e.g. trazodone and lorcaserin. Coincident with these zebrafish findings, we treated five medically intractable Dravet syndrome patients with a clinically-approved serotonin receptor agonist (lorcaserin, Belviq®) and observed some promising results in terms of reductions in seizure frequency and/or severity. Our findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet syndrome.

Topics: Adolescent; Animals; Animals, Genetically Modified; Anticonvulsants; Benzazepines; Benzimidazoles; Child; Disease Models, Animal; Epilepsies, Myoclonic; Female; Gene Expression Regulation, Developmental; Humans; Larva; Male; NAV1.1 Voltage-Gated Sodium Channel; Protein Binding; Receptors, Serotonin; Seizures; Serotonin; Signal Transduction; Treatment Outcome; Zebrafish