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

Connexin 43 hemichannels and pannexin‐1 channels contribute to the α‐synuclein‐induced dysfunction and death of astrocytes

“…Astrocyte coupling via gap junctions determines the propagation of intercellular Ca 2+ waves and spatial buffering of neurotransmitters, K + and H + , thus sculpting an extracellular environment that ensures proper neuronal function (De Bock et al, ). Because the increased opening of hemichannels and pannexons may take place in parallel with astroglial uncoupling (Avendano et al, ; Gajardo‐Gomez et al, ; Retamal et al, ), we explored whether the functional state of astroglial gap junctions is disturbed by α‐synuclein. Similar to prior studies (Avendano et al, ), control astrocytes display a strong intercellular coupling to LY (Figure a).…”

“…The activity of hemichannels and pannexons could rely on augments in the open probability per channel, conductance/selectivity and/or the number of channels at the plasma membrane. Prior evidence has linked the channel‐dependent Etd uptake with increased surface levels of Cx43 and Panx1 in different cell types (Avendano et al, ; Gajardo‐Gomez et al, ) or increase in open probability without changes in the total amount of Cx43 in the cell surface (Schalper et al, ). Here, we evaluated whether the α‐synuclein‐mediated Etd uptake correlates with changes in total and/or surface amount of Cx43 and Panx1.…”

“…Scenarios of inflammation often cause an increased hemichannel and/or pannexon‐dependent release of glutamate and ATP from astrocytes (Avendano et al, ; Gajardo‐Gomez et al, ; Orellana et al, ). Given that glutamatergic and purinergic signaling participates in the opening of astroglial hemichannels and pannexons (Iglesias et al, ; Orellana et al, , ), we evaluated whether α‐synuclein affects the release of glutamate and ATP from astrocytes.…”

Endocannabinoid system in neurodegenerative disorders

“…Similarly, treatment with WIN, 2‐AG, or methanandamide prevented the hemichannel activity and inflammatory profile induced by Aβ in astrocytes; excitotoxic glutamate release and neuronal damage in hippocampal slices treated with Aβ (Gajardo‐Gomez et al . ). Notably, CB2R and the AEA‐hydrolyzing enzyme FAAH have been shown to be selectively expressed in astrocytes and microglia associated with neuritic plaques (Benito et al .…”

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

“…Relevant to this point, increased levels of [Ca 2+ ] i , iNOS, and COX 2 activation, as well as production of NO, underpin the Panx1 channel-dependent release of ATP in LPS-stimulated microglia (Orellana et al, 2013), whereas NO-mediated Cx43 s-nitrosylation is pivotal in the activation of astroglial hemichannels triggered by oxidative stress (Retamal et al, 2006). Importantly, the stimulation of these pathways has been linked to glial hemichannel/pannexon activation under different pathological conditions, including amyloid β treatment (Gajardo-Gómez et al, 2017), prenatal inflammation (Avendaño et al, 2015), restraint stress (Orellana et al, 2015), spinal cord injury (Garré et al, 2016), high cholesterol diet (Orellana et al, 2014b), AD (Yi et al, 2016), and Niemann-Pick type C disease (Sáez et al, 2013). …”