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Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis.

Del Rio R, Quintanilla RA, Orellana JA, Retamal MA - Front Physiol (2015)

Bottom Line: One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system.Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells.In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigación Biomédica, Universidad Autónoma de Chile Santiago, Chile ; Dirección de Investigación, Universidad Científica del Sur Lima, Perú

ABSTRACT
Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

No MeSH data available.


Related in: MedlinePlus

Possible actions of metabolic syndrome on glia-to-neuron communication mediated by hemichannels. Metabolic syndrome (MS) may induce a generalized inflammatory state that could affect the nervous system (1). In this context, autocrine/paracrine release of pro-inflammatory cytokines (e.g., IL-1β and TNF-α) by reactive glial cells could lead to the activation of a p38MAPK/iNOS-dependent pathway and further production of nitric oxide (NO) (2). NO could cause the nitrosilation of Cx43, resulting in opening of Cx43 glial cell hemichannels (3). Alternatively, for an unknown mechanism, NO could increase the activity of Panx1 hemichannels. Along with the systemic inflammatory state, MS impairs mitochondrial function in glial cells, leading to redox potential imbalance and subsequent uncontrolled production of reactive oxygen species (ROS) (4). Modulation of oxidative status of Cx43 and/or Panx1 hemichannels by ROS could increase their activity (5). High levels of triglycerides and fatty acids during the progression of MS could directly enhance the opening of hemichannels in glial cells (6). In addition, paracrine release of gliotransmitters through glial cell hemichannels (e.g., ATP, glutamate, D-serine) (7) could act on neighboring or distant neurons, resulting in the activation of P2X7 and NMDA receptors (8). The latter increase levels of [Ca2+]i, (9) and thereof the activity of neuronal Panx1 channels, resulting in neuronal function impairment and cell death (10).
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Figure 2: Possible actions of metabolic syndrome on glia-to-neuron communication mediated by hemichannels. Metabolic syndrome (MS) may induce a generalized inflammatory state that could affect the nervous system (1). In this context, autocrine/paracrine release of pro-inflammatory cytokines (e.g., IL-1β and TNF-α) by reactive glial cells could lead to the activation of a p38MAPK/iNOS-dependent pathway and further production of nitric oxide (NO) (2). NO could cause the nitrosilation of Cx43, resulting in opening of Cx43 glial cell hemichannels (3). Alternatively, for an unknown mechanism, NO could increase the activity of Panx1 hemichannels. Along with the systemic inflammatory state, MS impairs mitochondrial function in glial cells, leading to redox potential imbalance and subsequent uncontrolled production of reactive oxygen species (ROS) (4). Modulation of oxidative status of Cx43 and/or Panx1 hemichannels by ROS could increase their activity (5). High levels of triglycerides and fatty acids during the progression of MS could directly enhance the opening of hemichannels in glial cells (6). In addition, paracrine release of gliotransmitters through glial cell hemichannels (e.g., ATP, glutamate, D-serine) (7) could act on neighboring or distant neurons, resulting in the activation of P2X7 and NMDA receptors (8). The latter increase levels of [Ca2+]i, (9) and thereof the activity of neuronal Panx1 channels, resulting in neuronal function impairment and cell death (10).

Mentions: Until this point we discussed the possible mechanism that associates glial cell hemichannel opening with the increased sympathetic activation observed during the MS. This hypothesis could plausible if hemichannel opening increases until certain (unknown) level. However, what about if hemichannel activity increase even more? The most obvious suggestion is that neuronal function and synaptic transmission will be compromised, resulting in further production of neuropathies (Retamal et al., 2015). It is well known that metabolic-associated diseases can produce the appearance of neuropathies (Kim and Feldman, 2012; D'Amico and Bertini, 2013). One possibility is that gliotransmitters released from glial cells due to hemichannel opening become neurotoxic, as has been recently demonstrated (Orellana et al., 2011a,b; Avendaño et al., 2015). In summary, we propose that under MS a positive feedback loop can be generated between reactive gliosis, inflammation, mitochondrial dysfunction and hemichannel opening (Figure 2). The latter may contribute to the autonomic imbalance at early stages of MS specifically through a glial cell dependent modulation of sympathetic neuron activity in the brainstem. Importantly, as the disease progress, development of neuropathies could take place mainly associated with the neurotoxic consequence of a massive opening of hemichannels.


Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis.

Del Rio R, Quintanilla RA, Orellana JA, Retamal MA - Front Physiol (2015)

Possible actions of metabolic syndrome on glia-to-neuron communication mediated by hemichannels. Metabolic syndrome (MS) may induce a generalized inflammatory state that could affect the nervous system (1). In this context, autocrine/paracrine release of pro-inflammatory cytokines (e.g., IL-1β and TNF-α) by reactive glial cells could lead to the activation of a p38MAPK/iNOS-dependent pathway and further production of nitric oxide (NO) (2). NO could cause the nitrosilation of Cx43, resulting in opening of Cx43 glial cell hemichannels (3). Alternatively, for an unknown mechanism, NO could increase the activity of Panx1 hemichannels. Along with the systemic inflammatory state, MS impairs mitochondrial function in glial cells, leading to redox potential imbalance and subsequent uncontrolled production of reactive oxygen species (ROS) (4). Modulation of oxidative status of Cx43 and/or Panx1 hemichannels by ROS could increase their activity (5). High levels of triglycerides and fatty acids during the progression of MS could directly enhance the opening of hemichannels in glial cells (6). In addition, paracrine release of gliotransmitters through glial cell hemichannels (e.g., ATP, glutamate, D-serine) (7) could act on neighboring or distant neurons, resulting in the activation of P2X7 and NMDA receptors (8). The latter increase levels of [Ca2+]i, (9) and thereof the activity of neuronal Panx1 channels, resulting in neuronal function impairment and cell death (10).
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Related In: Results  -  Collection

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Figure 2: Possible actions of metabolic syndrome on glia-to-neuron communication mediated by hemichannels. Metabolic syndrome (MS) may induce a generalized inflammatory state that could affect the nervous system (1). In this context, autocrine/paracrine release of pro-inflammatory cytokines (e.g., IL-1β and TNF-α) by reactive glial cells could lead to the activation of a p38MAPK/iNOS-dependent pathway and further production of nitric oxide (NO) (2). NO could cause the nitrosilation of Cx43, resulting in opening of Cx43 glial cell hemichannels (3). Alternatively, for an unknown mechanism, NO could increase the activity of Panx1 hemichannels. Along with the systemic inflammatory state, MS impairs mitochondrial function in glial cells, leading to redox potential imbalance and subsequent uncontrolled production of reactive oxygen species (ROS) (4). Modulation of oxidative status of Cx43 and/or Panx1 hemichannels by ROS could increase their activity (5). High levels of triglycerides and fatty acids during the progression of MS could directly enhance the opening of hemichannels in glial cells (6). In addition, paracrine release of gliotransmitters through glial cell hemichannels (e.g., ATP, glutamate, D-serine) (7) could act on neighboring or distant neurons, resulting in the activation of P2X7 and NMDA receptors (8). The latter increase levels of [Ca2+]i, (9) and thereof the activity of neuronal Panx1 channels, resulting in neuronal function impairment and cell death (10).
Mentions: Until this point we discussed the possible mechanism that associates glial cell hemichannel opening with the increased sympathetic activation observed during the MS. This hypothesis could plausible if hemichannel opening increases until certain (unknown) level. However, what about if hemichannel activity increase even more? The most obvious suggestion is that neuronal function and synaptic transmission will be compromised, resulting in further production of neuropathies (Retamal et al., 2015). It is well known that metabolic-associated diseases can produce the appearance of neuropathies (Kim and Feldman, 2012; D'Amico and Bertini, 2013). One possibility is that gliotransmitters released from glial cells due to hemichannel opening become neurotoxic, as has been recently demonstrated (Orellana et al., 2011a,b; Avendaño et al., 2015). In summary, we propose that under MS a positive feedback loop can be generated between reactive gliosis, inflammation, mitochondrial dysfunction and hemichannel opening (Figure 2). The latter may contribute to the autonomic imbalance at early stages of MS specifically through a glial cell dependent modulation of sympathetic neuron activity in the brainstem. Importantly, as the disease progress, development of neuropathies could take place mainly associated with the neurotoxic consequence of a massive opening of hemichannels.

Bottom Line: One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system.Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells.In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigación Biomédica, Universidad Autónoma de Chile Santiago, Chile ; Dirección de Investigación, Universidad Científica del Sur Lima, Perú

ABSTRACT
Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

No MeSH data available.


Related in: MedlinePlus