Connexin43 hemichannel inhibition exerts anticonvulsant effects against experimentally induced seizures
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1
Vrije Universiteit Brussel, Pharmaceutical Chemistry, Drug Analysis and Drug Information, Belgium
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2
Vrije Universiteit Brussel, Department of In Vitro Toxicology and Dermato-Cosmetology, Belgium
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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
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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