title: Cannabinoids prevent the amyloid β-induced activation of astroglial hemichannels: A neuroprotective mechanism.
abstract: The mechanisms involved in Alzheimer's disease are not completely understood and how astrocytes and their gliotransmission contribute to this neurodegenerative disease remains to be fully elucidated. Previous studies have shown that amyloid-β peptide (Aβ) induces neuronal death by a mechanism that involves the excitotoxic release of ATP and glutamate associated to astroglial hemichannel opening. We have demonstrated that synthetic and endogenous cannabinoids (CBs) reduce the opening of astrocyte Cx43 hemichannels evoked by activated microglia or inflammatory mediators. Nevertheless, whether CBs could prevent the astroglial hemichannel-dependent death of neurons evoked by Aβ is unknown. Astrocytes as well as acute hippocampal slices were treated with the active fragment of Aβ alone or in combination with the following CBs: WIN, 2-AG, or methanandamide (Meth). Hemichannel activity was monitored by single channel recordings and by time-lapse ethidium uptake while neuronal death was assessed by Fluoro-Jade C staining. We report that CBs fully prevented the hemichannel activity and inflammatory profile evoked by Aβ in astrocytes. Moreover, CBs fully abolished the Aβ-induced release of excitotoxic glutamate and ATP associated to astrocyte Cx43 hemichannel activity, as well as neuronal damage in hippocampal slices exposed to Aβ. Consequently, this work opens novel avenues for alternative treatments that target astrocytes to maintain neuronal function and survival during AD. GLIA 2016 GLIA 2017;65:122-137.
authors.affiliation: Departamento de Neurología; Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Rosario
authors.initials: R
authors.lastname: Gajardo-Gómez
authors.affiliation: Departamento de Neurología; Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Valeria C
authors.initials: VC
authors.lastname: Labra
authors.affiliation: Departamento de Neurología; Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Carola J
authors.initials: CJ
authors.lastname: Maturana
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile and Instituto Milenio, Centro Interdisciplinario de Neurociencias de Valparaíso, Chile.
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Shoji
authors.affiliation: Departamento de Neurología; Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Santibañez
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile and Instituto Milenio, Centro Interdisciplinario de Neurociencias de Valparaíso, Chile.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France/Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, Institut National de la Santé et de la Recherche Médicale U1050, Paris Cedex 05, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
authors.affiliation: Departamento de Neurología; Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Orellana
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002186:Cannabinoids; D017630:Connexins; D018698:Glutamic Acid
keywords: alzheimer; connexin43; glia; neuroinflammation; neuron