Cannabinoids Prevent the Amyloid β-Induced Activation of Astroglial Hemichannels: A Neuroprotective Mechanism

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-beta peptide Ab) 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 A beta is unknown. Astrocytes as well as acute hippocampal slices were treated with the active fragment of A beta 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 Ab in astrocytes. Moreover, CBs fully abolished the A beta-induced release of excitotoxic glutamate and ATP associated to astrocyte Cx43 hemichannel activity, as well as neuronal damage in hippocampal slices exposed to Ab. Consequently, this work opens novel avenues for alternative treatments that target astrocytes to maintain neuronal function and survival during AD.