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Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases.

Takeuchi H, Suzumura A - Front Cell Neurosci (2014)

Bottom Line: The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects.We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface.Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University Nagoya, Japan.

ABSTRACT
Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g., minocycline) have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

The vicious spiral of neuroinflammation and neurodegeneration mediated by gap junctions and hemichannels. Microglial glutamate release via hemichannels initiates neuronal damage. Then, waves of death signals are propagated and amplified via glial and neuronal gap-junction communication. Chemoattractants from damaged cells induce infiltration by microglia and macrophages. These infiltrating cells initiate further neuronal damage and enlarge the lesion of neuroinflammation and neurodegeneration. This vicious spiral of neuroinflammation and neurodegeneration may be involved in the progression of various neurologic diseases.
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Figure 3: The vicious spiral of neuroinflammation and neurodegeneration mediated by gap junctions and hemichannels. Microglial glutamate release via hemichannels initiates neuronal damage. Then, waves of death signals are propagated and amplified via glial and neuronal gap-junction communication. Chemoattractants from damaged cells induce infiltration by microglia and macrophages. These infiltrating cells initiate further neuronal damage and enlarge the lesion of neuroinflammation and neurodegeneration. This vicious spiral of neuroinflammation and neurodegeneration may be involved in the progression of various neurologic diseases.

Mentions: As mentioned above, glial gap junctions play an important role in maintenance of homeostasis in the CNS under the physiological conditions. These structures, however, also contribute to the initiation and propagation of pathologic conditions (Orellana et al., 2009). Stroke and trauma provide examples that illustrate this mechanism. Ischemia or contusion leads to a rapid decrease in intracellular oxygen levels and subsequent reduction in ATP synthesis, resulting in eventual cell death (Kalogeris et al., 2012). Injured cells contain toxic ions and molecules at high concentrations (e.g., Ca2+, K+, ROS, and NO). These toxic molecules are propagated from injured cells to healthier cells through gap junctions. Ischemic conditions also induce uncoupled hemichannels to open, leading to paracrine transfer of toxic molecules (Thompson et al., 2006; De Vuyst et al., 2007). These waves of death signals activate astrocytes and microglia, inducing the release of toxic molecules including glutamate, ROS, NO, and pro-inflammatory cytokines and chemokines. This vicious amplification spiral of signaling could worsen neuroinflammation by recruiting leukocytes and increasing the lesion area (Orellana et al., 2009) (Figure 3). Moreover, gap junction and hemichannel blockers have exerted therapeutic effects in experimental models of stroke and spinal cord injury (Rawanduzy et al., 1997; Frantseva et al., 2002; De Pina-Benabou et al., 2005; Takeuchi et al., 2008a; Tamura et al., 2011; Huang et al., 2012; Umebayashi et al., 2014).


Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases.

Takeuchi H, Suzumura A - Front Cell Neurosci (2014)

The vicious spiral of neuroinflammation and neurodegeneration mediated by gap junctions and hemichannels. Microglial glutamate release via hemichannels initiates neuronal damage. Then, waves of death signals are propagated and amplified via glial and neuronal gap-junction communication. Chemoattractants from damaged cells induce infiltration by microglia and macrophages. These infiltrating cells initiate further neuronal damage and enlarge the lesion of neuroinflammation and neurodegeneration. This vicious spiral of neuroinflammation and neurodegeneration may be involved in the progression of various neurologic diseases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151093&req=5

Figure 3: The vicious spiral of neuroinflammation and neurodegeneration mediated by gap junctions and hemichannels. Microglial glutamate release via hemichannels initiates neuronal damage. Then, waves of death signals are propagated and amplified via glial and neuronal gap-junction communication. Chemoattractants from damaged cells induce infiltration by microglia and macrophages. These infiltrating cells initiate further neuronal damage and enlarge the lesion of neuroinflammation and neurodegeneration. This vicious spiral of neuroinflammation and neurodegeneration may be involved in the progression of various neurologic diseases.
Mentions: As mentioned above, glial gap junctions play an important role in maintenance of homeostasis in the CNS under the physiological conditions. These structures, however, also contribute to the initiation and propagation of pathologic conditions (Orellana et al., 2009). Stroke and trauma provide examples that illustrate this mechanism. Ischemia or contusion leads to a rapid decrease in intracellular oxygen levels and subsequent reduction in ATP synthesis, resulting in eventual cell death (Kalogeris et al., 2012). Injured cells contain toxic ions and molecules at high concentrations (e.g., Ca2+, K+, ROS, and NO). These toxic molecules are propagated from injured cells to healthier cells through gap junctions. Ischemic conditions also induce uncoupled hemichannels to open, leading to paracrine transfer of toxic molecules (Thompson et al., 2006; De Vuyst et al., 2007). These waves of death signals activate astrocytes and microglia, inducing the release of toxic molecules including glutamate, ROS, NO, and pro-inflammatory cytokines and chemokines. This vicious amplification spiral of signaling could worsen neuroinflammation by recruiting leukocytes and increasing the lesion area (Orellana et al., 2009) (Figure 3). Moreover, gap junction and hemichannel blockers have exerted therapeutic effects in experimental models of stroke and spinal cord injury (Rawanduzy et al., 1997; Frantseva et al., 2002; De Pina-Benabou et al., 2005; Takeuchi et al., 2008a; Tamura et al., 2011; Huang et al., 2012; Umebayashi et al., 2014).

Bottom Line: The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects.We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface.Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University Nagoya, Japan.

ABSTRACT
Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g., minocycline) have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus