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      Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B

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          Abstract

          There is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus Aspergillus insuetus. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery.

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          Most cited references47

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          Epilepsy: new advances.

          Epilepsy affects 65 million people worldwide and entails a major burden in seizure-related disability, mortality, comorbidities, stigma, and costs. In the past decade, important advances have been made in the understanding of the pathophysiological mechanisms of the disease and factors affecting its prognosis. These advances have translated into new conceptual and operational definitions of epilepsy in addition to revised criteria and terminology for its diagnosis and classification. Although the number of available antiepileptic drugs has increased substantially during the past 20 years, about a third of patients remain resistant to medical treatment. Despite improved effectiveness of surgical procedures, with more than half of operated patients achieving long-term freedom from seizures, epilepsy surgery is still done in a small subset of drug-resistant patients. The lives of most people with epilepsy continue to be adversely affected by gaps in knowledge, diagnosis, treatment, advocacy, education, legislation, and research. Concerted actions to address these challenges are urgently needed.
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            Deep, diverse and definitely different: unique attributes of the world's largest ecosystem

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              Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression.

              Rodent seizure models have significantly contributed to our basic understanding of epilepsy. However, medically intractable forms of epilepsy persist and the fundamental mechanisms underlying this disease remain unclear. Here we show that seizures can be elicited in a simple vertebrate system e.g. zebrafish larvae (Danio rerio). Exposure to a common convulsant agent (pentylenetetrazole, PTZ) induced a stereotyped and concentration-dependent sequence of behavioral changes culminating in clonus-like convulsions. Extracellular recordings from fish optic tectum revealed ictal and interictal-like electrographic discharges after application of PTZ, which could be blocked by tetrodotoxin or glutamate receptor antagonists. Epileptiform discharges were suppressed by commonly used antiepileptic drugs, valproate and diazepam, in a concentration-dependent manner. Up-regulation of c-fos expression was also observed in CNS structures of zebrafish exposed to PTZ. Taken together, these results demonstrate that chemically-induced seizures in zebrafish exhibit behavioral, electrographic, and molecular changes that would be expected from a rodent seizure model. Therefore, zebrafish larvae represent a powerful new system to study the underlying basis of seizure generation, epilepsy and epileptogenesis.
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                Author and article information

                Journal
                Mar Drugs
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                25 October 2019
                November 2019
                : 17
                : 11
                : 607
                Affiliations
                [1 ]Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, Belgium; danielle.copmans@ 123456kuleuven.be (D.C.); monika.slezak@ 123456wp.pl (M.Ś.); Nina.Dirkx@ 123456uantwerpen.be (N.D.); michele.partoens@ 123456kuleuven.be (M.P.); c.v.esguerra@ 123456farmasi.uio.no (C.V.E.); alexander.dettmar.crawford@ 123456nmbu.no (A.D.C.)
                [2 ]Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, 2800 Kgs. Lyngby, Denmark; sarakildgaard@ 123456gmail.com (S.K.); silas.anselm@ 123456gmail.com (S.A.R.)
                [3 ]Current affiliation: Centre for Molecular Medicine Norway, Faculty of Medicine, University of Oslo, Gaustadalléen 21, 0349 Oslo, Norway
                [4 ]Current affiliation: Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ullevålsveien 72, 0454 Oslo, Norway
                Author notes
                [* ]Correspondence: tol@ 123456bio.dtu.dk (T.O.L.); peter.dewitte@ 123456kuleuven.be (P.A.M.-d.W.); Tel.: +45-4525-2632 (T.O.L.); +32-16-32-34-32 (P.A.M.-d.W.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-9804-8410
                https://orcid.org/0000-0002-9989-9567
                Article
                marinedrugs-17-00607
                10.3390/md17110607
                6891649
                31731399
                e3b66dad-04df-4234-8ecc-5d7dfe31d958
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 September 2019
                : 21 October 2019
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                pharmasea,epilepsy,zebrafish,marine drug discovery,isoquinoline alkaloids,tmc-120a,tmc-120b,tmc-120c,penicisochroman g,ustusorane b

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