Activity of Drugs and Components of Natural Origin in the Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome)

Berio, A; Piazzi, A

doi:10.2174/1871524915666150430161321

Cited by 6 publications

(5 citation statements)

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“…Screening for antiseizure compounds using zebrafish larvae, locomotor assays are typically followed by brain activity measurements, thereby reducing the possibility to find false positive hits . This paired selection criterion is however somewhat in contrast to the clinical setting, where AEDs often suppress seizures but do not dramatically decrease events on the electroencephalogram (EEG) . So it remains to be seen whether 5-HT 1E - and 5-HT 7 -agonists are truly false positive hits, as the present results would seem to indicate, or whether they are potential interesting pharmacological tools in the treatment of DS.…”

Section: Resultsmentioning

confidence: 86%

Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model

Sourbron

Schneider

Kecskés

et al. 2016

ACS Chem. Neurosci.

120

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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 potentials in the zebrafish larval forebrain, we confirmed the antiepileptiform activity of the 5-HT1D-, 5-HT2C-, and especially the 5-HT2A-agonist. Interestingly, we also found a significant decrease of serotonin in the heads of homozygous scn1Lab(-/-) mutants as compared to the wild type zebrafish, which suggest that neurochemical defects might play a crucial role in the pathophysiology of DS. Taken together, our results emphasize the high conservation of the serotonergic receptors in zebrafish larvae. Modulating certain serotonergic receptors was shown to effectively reduce seizures. Our findings therefore open new avenues for the development of future novel DS therapeutics.

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Section: Resultsmentioning

confidence: 86%

Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model

Sourbron

Schneider

Kecskés

et al. 2016

ACS Chem. Neurosci.

120

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“…The loss of this interaction may also explain the severe cognitive impairment observed in both ID patients. Mutations in SCN1A , coding for the voltage‐gated sodium channel Nav1.1, are associated with severe cognitive impairment and seizures (Bender, Luikart, & Lenck‐Santini, ), as well as with severe myoclonic epilepsy of infancy (Berio & Piazzi, ).…”

Section: Discussionmentioning

confidence: 99%

CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy

et al. 2017

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De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the β subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the α subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the β subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.

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“…Even though we underline that the above-mentioned paired selection criterion (locomotor and brain activity assays) is validated in zebrafish epilepsy research, it is different from the clinical setting where ASM can suppress seizures without reducing epileptic events on the electroencephalogram [144,145]. The integrated Zebrafish Analysis Platform (iZAP), constructed by Hong et al [142] is a novel multichannel electrophysiology unit that can measure brain activities of multiple zebrafish larvae at once.…”

Section: Two-stage Locomotor and Electrophysiological Setupmentioning

confidence: 99%

“…Moreover, homozygous scn1lab −/− mutants can phenotypically be distinguished from wildtype by their darker appearance, the absence of a swim bladder and a slight body curvature [138], which is not the case for homozygous scn1laa −/− mutants. Thus, this relatively higher identity percentage and distinct phenotype has boosted the use of scn1lab −/− mutants as a zebrafish DS model [117,142,145,250,264,[269][270][271]. The reason of this darker pigmentation could be the upregulation of melanocortin 5a, although the exact meaning of this upregulation remains unknown [138].…”

Section: Geneticsmentioning

confidence: 99%

Use of Zebrafish Models to Boost Research in Rare Genetic Diseases

Crouzier

Richard

Sourbron

et al. 2021

IJMS

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Rare genetic diseases are a group of pathologies with often unmet clinical needs. Even if rare by a single genetic disease (from 1/2000 to 1/more than 1,000,000), the total number of patients concerned account for approximatively 400 million peoples worldwide. Finding treatments remains challenging due to the complexity of these diseases, the small number of patients and the challenge in conducting clinical trials. Therefore, innovative preclinical research strategies are required. The zebrafish has emerged as a powerful animal model for investigating rare diseases. Zebrafish combines conserved vertebrate characteristics with high rate of breeding, limited housing requirements and low costs. More than 84% of human genes responsible for diseases present an orthologue, suggesting that the majority of genetic diseases could be modelized in zebrafish. In this review, we emphasize the unique advantages of zebrafish models over other in vivo models, particularly underlining the high throughput phenotypic capacity for therapeutic screening. We briefly introduce how the generation of zebrafish transgenic lines by gene-modulating technologies can be used to model rare genetic diseases. Then, we describe how zebrafish could be phenotyped using state-of-the-art technologies. Two prototypic examples of rare diseases illustrate how zebrafish models could play a critical role in deciphering the underlying mechanisms of rare genetic diseases and their use to identify innovative therapeutic solutions.

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Activity of Drugs and Components of Natural Origin in the Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome)

Cited by 6 publications

References 0 publications

Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model

Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model

CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy

Use of Zebrafish Models to Boost Research in Rare Genetic Diseases

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