General anesthetics have differential inhibitory effects on gap junction channels and hemichannels in astrocytes and neurons

Abstract

Astrocytes represent a major non-neuronal cell population actively involved in brain functions and pathologies. They express a large amount of gap junction proteins that allow communication between adjacent glial cells and the formation of glial networks. In addition, these membrane proteins can also operate as hemichannels, through which "gliotransmitters" are released, and thus contribute to neuroglial interaction. There are now reports demonstrating that alterations of astroglial gap junction communication and/or hemichannel activity impact neuronal and synaptic activity. Two decades ago we reported that several general anesthetics inhibited gap junctions in primary cultures of astrocytes (Mantz et al., (1993) Anesthesiology 78(5):892-901). As there are increasing studies investigating neuroglial interactions in anesthetized mice, we here updated this previous study by employing acute cortical slices and by characterizing the effects of general anesthetics on both astroglial gap junctions and hemichannels. As hemichannel activity is not detected in cortical astrocytes under basal conditions, we treated acute slices with the endotoxin LPS or proinflammatory cytokines to induce hemichannel activity in astrocytes, which in turn activated neuronal hemichannels. We studied two extensively used anesthetics, propofol and ketamine, and the more recently developed dexmedetomidine. We report that these drugs have differential inhibitory effects on gap junctional communication and hemichannel activity in astrocytes when used in their respective, clinically relevant concentrations, and that dexmedetomidine appears to be the least effective on both channel functions. In addition, the three anesthetics have similar effects on neuronal hemichannels. Altogether, our observations may contribute to optimizing the selection of anesthetics for in vivo animal studies.

Connexin-Dependent Neuroglial Networking as a New Therapeutic Target

“…Neuronal activity leads to an up-regulation of astrocyte Cx expression and channel function (Rouach et al, 2000, 2004, 2008; Koulakoff et al, 2008; Giaume et al, 2010; Pannasch et al, 2011, 2012, 2014; Roux et al, 2011). Interestingly, certain CNS-targeting drugs also appear to impact astrocyte Cxs (Giaume and Liu, 2012; Liu et al, 2013, 2016; Duchêne et al, 2016; Jeanson et al, 2016a,b). As presented in the three panels and based on literature, it can be hypothesized that optimal neuronal reactivity could be associated with an optimal size of local astroglial network (B) , as too large (C) or too reduced (A) syncytium might not adequately fuel metabolically active synapses during treatment with CNS drugs.…”

“…The effects of numerous anesthetics on astroglial Cxs have been described for more than 20 years, notably in primary cultured astrocytes from the striatum or the cortex (Dermietzel et al, 1991; Mantz et al, 1993) or in astrocytes from cortical slices (Liu et al, 2013, 2016). Anaesthetics, either modulating GABA A [halothane (Dermietzel et al, 1991; He and Burt, 2000), enflurane, isoflurane, or propofol (Mantz et al, 1993)], GABA B receptors [sodium oxybate (Liu et al, 2013)], or NMDA (ketamine; Liu et al, 2016) or α2-adrenergic receptors (dexmedetomidine; Liu et al, 2016), show similar profiles, as they reduced astroglial GJ.…”

“…Anaesthetics, either modulating GABA A [halothane (Dermietzel et al, 1991; He and Burt, 2000), enflurane, isoflurane, or propofol (Mantz et al, 1993)], GABA B receptors [sodium oxybate (Liu et al, 2013)], or NMDA (ketamine; Liu et al, 2016) or α2-adrenergic receptors (dexmedetomidine; Liu et al, 2016), show similar profiles, as they reduced astroglial GJ. Conversely, modafinil, a wake-promoting drug widely used in narcolepsy (Barateau et al, 2016) with a complex mechanism of action (Minzenberg and Carter, 2008), enhances astroglial Cx and more precisely Cx30 expression and GJ function (Liu et al, 2013).…”

Targeting Connexin43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

“…In recent years, studies have indicated that Cx43-containing GJCs and Hcs are the main cell adhesion channels in astrocytes and maintain the homeostasis of the neural microenvironment in the CNS [10]. However, abnormal opening of Cx43Hcs on the surface of reactive astrocytes can release small molecules into the intercellular space under pathological conditions [33].These small molecules in uence the steady state of the cell microenvironment, which induces in ammatory and cell death programs by regulating the crosstalk between reactive astrocytes and other cells in the CNS [34]. De nite evidence has shown that like Cx43 overexpression, abnormal Cx43Hc opening leads to further brain damage in different CNS diseases.Suppressing pathological Cx43 expression can reduce the formation of hemichannels and promote the production of survival genes [35,36].Inhibition of Cx43Hcs with selective blockers has been shown to provide protective effects under different pathological stresses [37].Our previous research con rmed that Cx43Hc blockers signi cantly alleviate neurological de cits and infarct volume in a rodent model of ischemic stroke [12,38].To our knowledge,there have been no reports on the characteristics of Cx43Hcs after ICH injury.In our current study, sustained overexpression of Cx43 coupled with abnormal opening of Cx43Hcs was observed in a mouse model of ICH injury (Figure 1).…”

Role of Astroglial Hemichannels and Pannexons in Memory and Neurodegenerative Diseases

“…Recent in vitro studies have shown that astroglial Cx43 hemichannel activity changes in response to general anesthetics (Liu et al, 2016 ) antidepressants (Jeanson et al, 2015 ) and modafinil (Duchêne et al, 2016 ), suggesting that they may also be drug targets.…”