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Inhibition of astroglial connexin43 hemichannels with TAT-Gap19 exerts anticonvulsant effects in rodents

(2018) GLIA. 66(8). p.1788-1804
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Abstract
Accumulating evidence shows a key function for astrocytic connexin43 (Cx43) signaling in epilepsy. However, the lack of experimental distinction between Cx43 gap junction channels (GJCs) and hemichannels (HCs) has impeded the identification of the exact contribution of either channel configurations to epilepsy. We therefore investigated whether TAT-Gap19, a Cx mimetic peptide that inhibits Cx43 HCs but not the corresponding Cx43 GJCs, influences experimentally induced seizures in rodents. Dye uptake experiments in acute hippocampal slices of mice demonstrated that astroglial Cx43 HCs open in response to the chemoconvulsant pilocarpine and this was inhibited by TAT-Gap19. In vivo, pilocarpine-induced seizures as well as the accompanying increase in D-serine microdialysate levels were suppressed by Cx43 HC inhibition. Moreover, the anticonvulsant action of TAT-Gap19 was reversed by exogenous D-serine administration, suggesting that Cx43 HC inhibition protects against seizures by lowering extracellular D-serine levels. The anticonvulsive properties of Cx43 HC inhibition were further confirmed in electrical seizure mouse models, i.e. an acute 6 Hertz (Hz) model of refractory seizures and a chronic 6 Hz corneal kindling model. Collectively, these results indicate that Cx43 HCs play a role in seizures and underscore their potential as a novel and druggable target in epilepsy treatment.
Keywords
astrocytes, connexin43 hemichannels, pilocarpine, seizures, TAT-Gap19, AMINO-ACID OXIDASE, D-SERINE, GAP-JUNCTIONS, HIPPOCAMPAL ASTROCYTES, PANNEXIN HEMICHANNELS, SYNAPTIC-TRANSMISSION, CX43 HEMICHANNELS, SEIZURE ACTIVITY, ATP RELEASE, EPILEPSY

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Chicago
Walrave, Laura, Anouk Pierre, Giulia Albertini, Najat Aourz, Dimitri De Bundel, Ann Van Eeckhaut, Mathieu Vinken, Christian Giaume, Luc Leybaert, and Ilse Smolders. 2018. “Inhibition of Astroglial Connexin43 Hemichannels with TAT-Gap19 Exerts Anticonvulsant Effects in Rodents.” Glia 66 (8): 1788–1804.
APA
Walrave, L., Pierre, A., Albertini, G., Aourz, N., De Bundel, D., Van Eeckhaut, A., Vinken, M., et al. (2018). Inhibition of astroglial connexin43 hemichannels with TAT-Gap19 exerts anticonvulsant effects in rodents. GLIA, 66(8), 1788–1804.
Vancouver
1.
Walrave L, Pierre A, Albertini G, Aourz N, De Bundel D, Van Eeckhaut A, et al. Inhibition of astroglial connexin43 hemichannels with TAT-Gap19 exerts anticonvulsant effects in rodents. GLIA. 2018;66(8):1788–804.
MLA
Walrave, Laura et al. “Inhibition of Astroglial Connexin43 Hemichannels with TAT-Gap19 Exerts Anticonvulsant Effects in Rodents.” GLIA 66.8 (2018): 1788–1804. Print.
@article{8607700,
  abstract     = {Accumulating evidence shows a key function for astrocytic connexin43 (Cx43) signaling in epilepsy. However, the lack of experimental distinction between Cx43 gap junction channels (GJCs) and hemichannels (HCs) has impeded the identification of the exact contribution of either channel configurations to epilepsy. We therefore investigated whether TAT-Gap19, a Cx mimetic peptide that inhibits Cx43 HCs but not the corresponding Cx43 GJCs, influences experimentally induced seizures in rodents. Dye uptake experiments in acute hippocampal slices of mice demonstrated that astroglial Cx43 HCs open in response to the chemoconvulsant pilocarpine and this was inhibited by TAT-Gap19. In vivo, pilocarpine-induced seizures as well as the accompanying increase in D-serine microdialysate levels were suppressed by Cx43 HC inhibition. Moreover, the anticonvulsant action of TAT-Gap19 was reversed by exogenous D-serine administration, suggesting that Cx43 HC inhibition protects against seizures by lowering extracellular D-serine levels. The anticonvulsive properties of Cx43 HC inhibition were further confirmed in electrical seizure mouse models, i.e. an acute 6 Hertz (Hz) model of refractory seizures and a chronic 6 Hz corneal kindling model. Collectively, these results indicate that Cx43 HCs play a role in seizures and underscore their potential as a novel and druggable target in epilepsy treatment.},
  author       = {Walrave, Laura and Pierre, Anouk and Albertini, Giulia and Aourz, Najat and De Bundel, Dimitri and Van Eeckhaut, Ann and Vinken, Mathieu and Giaume, Christian and Leybaert, Luc and Smolders, Ilse},
  issn         = {0894-1491},
  journal      = {GLIA},
  keywords     = {astrocytes,connexin43 hemichannels,pilocarpine,seizures,TAT-Gap19,AMINO-ACID OXIDASE,D-SERINE,GAP-JUNCTIONS,HIPPOCAMPAL ASTROCYTES,PANNEXIN HEMICHANNELS,SYNAPTIC-TRANSMISSION,CX43 HEMICHANNELS,SEIZURE ACTIVITY,ATP RELEASE,EPILEPSY},
  language     = {eng},
  number       = {8},
  pages        = {1788--1804},
  title        = {Inhibition of astroglial connexin43 hemichannels with TAT-Gap19 exerts anticonvulsant effects in rodents},
  url          = {http://dx.doi.org/10.1002/glia.23341},
  volume       = {66},
  year         = {2018},
}

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