In epilepsy research, emphasis is put on exploring new anticonvulsant compounds with modes of action distinct from the clinically available anti- seizure drugs, to be able to treat therapy-resistant patients. In line with this notion, the main objective of this thesis work was to study glial connexin43 hemichannels (Cx43 HCs) as possible anti-seizure drug targets in several rodent models of seizures and epilepsy. As experimental tool we used the recently developed Cx43 mimetic peptide “TAT-Gap19” that blocks Cx43 HC function without reducing Cx43 gap junction-mediated intercellular communication. We demonstrated that TAT-Gap19 attenuates chemically- and electrically-induced seizures in rodents. Collectively, the results underscore the potential of Cx43 HCs as a novel and druggable target in epilepsy treatment. We also found that Cx43 HC inhibition impairs hippocampal short-term spatial memory, which should be considered for future research, since possible adverse effects on cognitive function might limit the clinical use. Nevertheless, the development of new therapeutic tools to selectively inhibit Cx43 HCs will make them promising targets for several diseases.
Connexin43 hemichannels as druggable targets for future anti-seizure medication.
Walrave, L. ((PhD) Student), Smolders, I. (Promotor), Vinken, M. (Co-promotor), Leybaert, L. (Co-promotor), Dupont, A. (Jury), Jansen, A. (Jury), Vander Heyden, Y. (Jury), Barker-Haliski, M. (Jury), Bedner, P. (Jury). 24 Jan 2019
Student thesis: Doctoral Thesis