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Implications of glial nitric oxide in neurodegenerative diseases.

Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F - Front Cell Neurosci (2015)

Bottom Line: The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation.Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death.This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Neurobiotechnology Group, Departament of Medicine, Facultat de Ciències de la Salut, Universitat Jaume I Castelló de la Plana, Spain.

ABSTRACT
Nitric oxide (NO) is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS) which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

Nitric oxide signaling pathway. Figure shows different steps in the NO signaling cascade and its interaction with several elements involved in the signaling pathway. NO is synthetized by two Ca2+-dependent or one independent Ca2+-mediated processes. First, (1) NOS1 or neuronal NOS (nNOS)-catalyzed reaction converts L-arginine into L-citrulline in the presence of O2, nicotinamide adenine dinucleotide phosphate (NADPH) and tertiary-butyl hydroperoxide (TBH) after the activation of the NMDA receptor by Ca2+. Also, (2) intracellular Ca2+ activates eNOS to release NO from brain microvessels. This NO binds to soluble guanylyl cylclase (sGC) receptors, which trigger a cGMP-dependent pathway and interacts with its downstream effectors (cGKI, CNG, PKG, PDE), the ultimate mediators of the NO’s physiological response. In addition, sGC is also critically affected by redox status. NO initiates the synthesis of ONOO− when O2− is present, which results in a dysfunctional uncouple variety of nitric oxide synthases (NOS) that produces O2− rather than NO. Finally, (3) NO is synthesized following the transcriptional expression of a Ca2+-independent iNOS isoform in glial cells, astrocytes and microglia after cytokine exposure.
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Figure 1: Nitric oxide signaling pathway. Figure shows different steps in the NO signaling cascade and its interaction with several elements involved in the signaling pathway. NO is synthetized by two Ca2+-dependent or one independent Ca2+-mediated processes. First, (1) NOS1 or neuronal NOS (nNOS)-catalyzed reaction converts L-arginine into L-citrulline in the presence of O2, nicotinamide adenine dinucleotide phosphate (NADPH) and tertiary-butyl hydroperoxide (TBH) after the activation of the NMDA receptor by Ca2+. Also, (2) intracellular Ca2+ activates eNOS to release NO from brain microvessels. This NO binds to soluble guanylyl cylclase (sGC) receptors, which trigger a cGMP-dependent pathway and interacts with its downstream effectors (cGKI, CNG, PKG, PDE), the ultimate mediators of the NO’s physiological response. In addition, sGC is also critically affected by redox status. NO initiates the synthesis of ONOO− when O2− is present, which results in a dysfunctional uncouple variety of nitric oxide synthases (NOS) that produces O2− rather than NO. Finally, (3) NO is synthesized following the transcriptional expression of a Ca2+-independent iNOS isoform in glial cells, astrocytes and microglia after cytokine exposure.

Mentions: To date, soluble guanylyl cyclase (sGC) is the most accepted physiological receptor described for NO. This receptor is formed by α and β subunits together with a prosthetic heme group with a ferrous iron. The binding of NO to this receptor activates the C-terminal catalytic domain, which produces guanosine 3′,5′-cyclic monophosphate (cGMP; Stamler et al., 1997). This enzyme activity is critically affected by redox status as the oxidation of the heme moiety on the β-subunit turns the enzyme sensitive to NO. There are other mechanisms by which oxidative stress may compromise this cGMP synthetic pathway (Figure 1). For instance, reactive oxidant peroxynitrite (ONOO−) induced by NO in the presence of superoxide (O2−) results in a dysfunctional uncouple variety of NOS that produces O2− rather than NO under oxidative stress (Xia et al., 1998; Sasaki et al., 2008).


Implications of glial nitric oxide in neurodegenerative diseases.

Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F - Front Cell Neurosci (2015)

Nitric oxide signaling pathway. Figure shows different steps in the NO signaling cascade and its interaction with several elements involved in the signaling pathway. NO is synthetized by two Ca2+-dependent or one independent Ca2+-mediated processes. First, (1) NOS1 or neuronal NOS (nNOS)-catalyzed reaction converts L-arginine into L-citrulline in the presence of O2, nicotinamide adenine dinucleotide phosphate (NADPH) and tertiary-butyl hydroperoxide (TBH) after the activation of the NMDA receptor by Ca2+. Also, (2) intracellular Ca2+ activates eNOS to release NO from brain microvessels. This NO binds to soluble guanylyl cylclase (sGC) receptors, which trigger a cGMP-dependent pathway and interacts with its downstream effectors (cGKI, CNG, PKG, PDE), the ultimate mediators of the NO’s physiological response. In addition, sGC is also critically affected by redox status. NO initiates the synthesis of ONOO− when O2− is present, which results in a dysfunctional uncouple variety of nitric oxide synthases (NOS) that produces O2− rather than NO. Finally, (3) NO is synthesized following the transcriptional expression of a Ca2+-independent iNOS isoform in glial cells, astrocytes and microglia after cytokine exposure.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4538301&req=5

Figure 1: Nitric oxide signaling pathway. Figure shows different steps in the NO signaling cascade and its interaction with several elements involved in the signaling pathway. NO is synthetized by two Ca2+-dependent or one independent Ca2+-mediated processes. First, (1) NOS1 or neuronal NOS (nNOS)-catalyzed reaction converts L-arginine into L-citrulline in the presence of O2, nicotinamide adenine dinucleotide phosphate (NADPH) and tertiary-butyl hydroperoxide (TBH) after the activation of the NMDA receptor by Ca2+. Also, (2) intracellular Ca2+ activates eNOS to release NO from brain microvessels. This NO binds to soluble guanylyl cylclase (sGC) receptors, which trigger a cGMP-dependent pathway and interacts with its downstream effectors (cGKI, CNG, PKG, PDE), the ultimate mediators of the NO’s physiological response. In addition, sGC is also critically affected by redox status. NO initiates the synthesis of ONOO− when O2− is present, which results in a dysfunctional uncouple variety of nitric oxide synthases (NOS) that produces O2− rather than NO. Finally, (3) NO is synthesized following the transcriptional expression of a Ca2+-independent iNOS isoform in glial cells, astrocytes and microglia after cytokine exposure.
Mentions: To date, soluble guanylyl cyclase (sGC) is the most accepted physiological receptor described for NO. This receptor is formed by α and β subunits together with a prosthetic heme group with a ferrous iron. The binding of NO to this receptor activates the C-terminal catalytic domain, which produces guanosine 3′,5′-cyclic monophosphate (cGMP; Stamler et al., 1997). This enzyme activity is critically affected by redox status as the oxidation of the heme moiety on the β-subunit turns the enzyme sensitive to NO. There are other mechanisms by which oxidative stress may compromise this cGMP synthetic pathway (Figure 1). For instance, reactive oxidant peroxynitrite (ONOO−) induced by NO in the presence of superoxide (O2−) results in a dysfunctional uncouple variety of NOS that produces O2− rather than NO under oxidative stress (Xia et al., 1998; Sasaki et al., 2008).

Bottom Line: The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation.Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death.This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Neurobiotechnology Group, Departament of Medicine, Facultat de Ciències de la Salut, Universitat Jaume I Castelló de la Plana, Spain.

ABSTRACT
Nitric oxide (NO) is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS) which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus