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.
Original languageEnglish
DOIs
Publication statusPublished - 3 Jul 2016
EventBelgian Brain Council 2016: The gene-environment tango in the healthy and diseased brain - MICX - Mons International Congress Xperience, Mons, Belgium
Duration: 8 Oct 20168 Oct 2016
http://www.belgianbraincouncil.be/congress2016/

Conference

ConferenceBelgian Brain Council 2016
CountryBelgium
CityMons
Period8/10/168/10/16
Internet address

ID: 29606856