Connexin43 hemichannel inhibition exerts anticonvulsant effects against experimentally induced seizures

Event Abstract Back to Event Connexin43 hemichannel inhibition exerts anticonvulsant effects against experimentally induced seizures Laura Walrave1*, Mathieu Vinken2, Luc Leybaert3 and Ilse J. Smolders1 1 Vrije Universiteit Brussel, Pharmaceutical Chemistry, Drug Analysis and Drug Information, Belgium 2 Vrije Universiteit Brussel, Department of In Vitro Toxicology and Dermato-Cosmetology, Belgium 3 Universiteit Gent, Physiology group, Department of Basic Medical Sciences, Belgium Epilepsy is one of the most common chronic neurological disorders and is characterized by spontaneous, repetitive seizures. Despite the medical advances over the years, 30 % of patients still suffer from intolerable side effects or drug resistance. Pharmacoresistancy can mainly be explained by the similar mechanisms of action of the marketed drugs, which all act on neuronal targets. Hence, the emphasis in antiepileptic drug discovery is being placed in the discovery of compounds that have distinct profiles of activity than the currently available anti-epileptic drugs. Therefore in this study, we investigated (non-neuronal) astrocytic connexin43 (Cx43) hemichannels as a possible target to treat epilepsy. Cx43 hemichannels are built up by six Cx43 membrane proteins and are located between the astrocytic cytosol and extracellular environment. Various pathological stimuli can activate Cx43 hemichannel opening, leading to the release of small signaling molecules (gliotransmitters, e.g. glutamate, D-serine, adenosine triphosphate), which in their turn can influence neurotransmission and epileptic seizures. To assess the role of Cx43 hemichannels in seizures, we used a newly developed, selective Cx43 mimetic peptide that only inhibits Cx43 hemichannels, without interfering with Cx43 gap junction coupling. We found that this peptide exerts anticonvulsant effects in different acute models of seizures (i.e. the 6 Hz mouse model of refractory seizures and the focal pilocarpine rat/mouse model). Additionally, an anticonvulsant effect was found in a chronic electrical model of epilepsy (6 Hz corneal kindling mouse model of refractory seizures). In the future, it is of very high importance to unravel the potential role of Cx43 hemichannels in epileptogenesis. This study points out the essential role of astrocytes and Cx43 hemichannels in epilepsy and might lead to novel therapy strategies to treat pharmacoresistant patients. If the Cx43 mimetic peptide affects epileptogenesis, it can give rise to the discovery of disease-modifying and/or anti-epileptogenic drugs. Résumé en Français: Étude d’une nouvelle cible thérapeutique pour le traitement de l’épilepsie : la connexine43 L’épilepsie est une maladie neurologique très fréquente caractérisée par des crises convulsives spontanées et répétées. Malgré les progrès médicaux récents, 30% des patients souffrent encore d’effets secondaires ou de résistances aux médicaments prescrits contre l’épilepsie. Il est donc important de trouver de nouvelles cibles thérapeutiques. Dans ce travail, nous nous sommes intéressés à une protéine qui forme un canal dans la paroi des certaines cellules de notre cerveau : les astrocytes. La présence de ce canal permet la libération de molécules qui peuvent agir sur les neurones et induire ou exacerber les crises d’épilepsie. Nous avons testé une molécule capable de bloquer ce canal et avons démontré que cette molécule réduisait les crises d’épilepsie dans un modèle murin d’épilepsie résistante. Samenvatting in het Nederlands: Titel: Studie van een nieuwe therapeutische aanpak voor de behandeling van epilepsie: connexin43. Epilepsie is een veelvoorkomende neurologische ziekte die gepaard gaat met spontane en herhaalde stuiptrekkingen. Ondanks recente medische vooruitgang blijven 30% van de patiënten lijden onder bijwerkingen of reageren ze niet op de voorgeschreven medicatie tegen epilepsie. Nieuwe behandelingsvormen zijn dus noodzakelijk. In dit werk ging onze aandacht naar een proteïne die een kanaal vormt in de wand van bepaalde hersencellen: de astrocyten. Dit kanaal laat toe dat moleculen vrijkomen die invloed kunnen hebben op de neuronen en epilepsieaanvallen uitlokken of verergeren. We hebben een molecule getest die dit kanaal kan blokkeren en konden aantonen dat deze molecule de kans op een epilepsieaanval deed afnemen bij muizen met resistente epilepsie. Keywords: connexin43 hemichannels, Epilepsy, Animal Models, Seizures, Peptides Conference: 6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016. Presentation Type: Poster Presentation Topic: Brain and brain diseases: between heredity and environment Citation: Walrave L, Vinken M, Leybaert L and Smolders IJ (2016). Connexin43 hemichannel inhibition exerts anticonvulsant effects against experimentally induced seizures. Conference Abstract: 6th Belgian Brain Congress. doi: 10.3389/conf.fnagi.2016.03.00028 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Jun 2016; Published Online: 03 Jul 2016. * Correspondence: Miss. Laura Walrave, Vrije Universiteit Brussel, Pharmaceutical Chemistry, Drug Analysis and Drug Information, Jette, 1090, Belgium, laura.walrave@vub.ac.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Laura Walrave Mathieu Vinken Luc Leybaert Ilse J Smolders Google Laura Walrave Mathieu Vinken Luc Leybaert Ilse J Smolders Google Scholar Laura Walrave Mathieu Vinken Luc Leybaert Ilse J Smolders PubMed Laura Walrave Mathieu Vinken Luc Leybaert Ilse J Smolders Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Topic: Connexins and lens biology
Subfield: Molecular Biology
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences