title: Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuroprotective.
abstract: Astrocytes express high levels of connexin43, a protein that forms two types of channels: gap junction channels for direct intercellular communication, and hemichannels for exchanges with the extracellular space. Inflammation induces connexin43 hemichannel activation, which has been proposed to be involved in neuroglial interactions. Here, we investigated the contribution of connexin43 to NMDA-induced excitotoxicity in neuron/astrocyte co-cultures, after treatment with a pro-inflammatory cytokine mixture, containing TNF-alpha and IL1-beta (Mix), that stimulated astroglial connexin43 hemichannel activity. Interestingly, NMDA treatment induced a higher amount of neurotoxicity in Mix-treated co-cultures than in untreated ones, whereas this extent of neurotoxicity was absent in enriched neuron cultures or in co-cultures with connexin43 knock-out astrocytes. Furthermore, application of connexin43 hemichannel blockers or a synthetic cannabinoid prevented the Mix-induced potentiated NMDA neurotoxicity. Altogether, these data demonstrate that inflammation-induced astroglial hemichannel activation plays a critical role in neuronal death and suggest a neuroprotective role of connexin43 hemichannel blockade.
authors.affiliation: INSERM U840, Collège de France, 11 Place Marcelin Berthelot, 75231 Paris, Cedex 05, France. nicolas.froger@inserm.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Froger
authors.forename: Juan A
authors.initials: JA
authors.lastname: Orellana
authors.forename: Charles-Felix
authors.initials: CF
authors.lastname: Calvo
authors.forename: Edwige
authors.initials: E
authors.lastname: Amigou
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kozoriz
authors.forename: Christian C
authors.initials: CC
authors.lastname: Naus
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D018031:Connexin 43 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018031:Connexin 43; D016207:Cytokines; D005456:Fluorescent Dyes; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate