Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model
Jo Sourbron,Henning Schneider,Angela Kecskés,Yusu Liu,Ellen M. Buening,Lieven Lagae,Ilse Julia Smolders,Peter de Witte +7 more
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TLDR
This study examined which 5-HT receptor subtypes can be targeted to trigger antiseizure effects in homozygous scn1Lab(-/-) mutant zebrafish larvae that recapitulate DS well and confirmed the efficacy of fenfluramine as an antiepileptiform compound in zebra fish models of DS.Abstract:
Dravet syndrome (DS) is a severe epilepsy syndrome that starts within the first year of life. In a clinical study, add-on treatment with fenfluramine, a potent 5-hydroxytryptamine (5-HT) releaser activating multiple 5-HT receptor subtypes, made 70% of DS children seizure free. Others and we recently confirmed the efficacy of fenfluramine as an antiepileptiform compound in zebrafish models of DS. By using a large set of subtype selective agonists, in this study we examined which 5-HT receptor subtypes can be targeted to trigger antiseizure effects in homozygous scn1Lab–/– mutant zebrafish larvae that recapitulate DS well. We also provide evidence that zebrafish larvae express the orthologues of all human 5-HT receptor subtypes. Using an automated larval locomotor behavior assay, we were able to show that selective 5-HT1D-, 5-HT1E-, 5-HT2A-, 5-HT2C-, and 5-HT7-agonists significantly decreased epileptiform activity in the mutant zebrafish at 7 days post fertilization (dpf). By measuring local field potential...read more
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Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome
TL;DR: The findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet syndrome, and it is demonstrated that clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways.
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Pharmacology of cannabinoids in the treatment of epilepsy.
Tyler E. Gaston,Daniel Friedman +1 more
TL;DR: As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions.
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Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development.
Meir Bialer,Svein I. Johannessen,Matthias J. Koepp,René H. Levy,Emilio Perucca,Piero Perucca,Piero Perucca,Torbjörn Tomson,H. Steve White +8 more
TL;DR: There continues to be a steady flow of potential antiepileptic drugs progressing to clinical development, and many of these compounds show innovative mechanisms of action, and some have already been tested in placebo‐controlled randomized controlled trials, with promising efficacy and safety results.
Journal ArticleDOI
dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice.
Gaia Colasante,Gabriele Lignani,Simone Brusco,Claudia Di Berardino,Jenna C Carpenter,Serena Giannelli,Nicholas Valassina,Simone Bido,Raffaele Ricci,Valerio Castoldi,Silvia Marenna,Timothy Church,Luca Massimino,Giuseppe Morabito,Fabio Benfenati,Fabio Benfenati,Stephanie Schorge,Letizia Leocani,Dimitri M. Kullmann,Vania Broccoli +19 more
TL;DR: The results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach to DS and other disorders resulting from altered gene dosage.
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Pharmacogenomics in epilepsy
TL;DR: ‘Precision medicine’ focuses on the identification of an underlying genetic aetiology allowing personalised therapeutic choices, and certain human leukocyte antigen, HLA, alleles are associated with an increased risk of idiosyncratic adverse drug reactions.
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Journal ArticleDOI
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Journal ArticleDOI
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Richard B. Rothman,Michael H. Baumann,Jason E. Savage,Laura Rauser,Ace McBride,Sandra J. Hufeisen,Bryan L. Roth +6 more
TL;DR: It is suggested that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at5-HT1B receptors.
Journal ArticleDOI
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TL;DR: A critical role for NaV1.1 channels in neuropsychiatric functions is demonstrated and a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviours in Dravet’s syndrome is provided.