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Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders

View Article: PubMed Central - PubMed

ABSTRACT

Guanosine is a purine nucleoside with important functions in cell metabolism and a protective role in response to degenerative diseases or injury. The past decade has seen major advances in identifying the modulatory role of extracellular action of guanosine in the central nervous system (CNS). Evidence from rodent and cell models show a number of neurotrophic and neuroprotective effects of guanosine preventing deleterious consequences of seizures, spinal cord injury, pain, mood disorders and aging-related diseases, such as ischemia, Parkinson’s and Alzheimer’s diseases. The present review describes the findings of in vivo and in vitro studies and offers an update of guanosine effects in the CNS. We address the protein targets for guanosine action and its interaction with glutamatergic and adenosinergic systems and with calcium-activated potassium channels. We also discuss the intracellular mechanisms modulated by guanosine preventing oxidative damage, mitochondrial dysfunction, inflammatory burden and modulation of glutamate transport. New and exciting avenues for future investigation into the protective effects of guanosine include characterization of a selective guanosine receptor. A better understanding of the neuromodulatory action of guanosine will allow the development of therapeutic approach to brain diseases.

No MeSH data available.


Overview of the main mechanisms involved in the neuroprotective effects of guanosine. Guanosine promotes neuroprotection through reduction of reactive oxygen species levels (ROS) by inhibition of nuclear factor kappa B (NF-κB) activation via MAPK/ERK and by preventing iNOS induction (1) [124]. Guanosine also counteracts ROS production by increasing antioxidant defenses [i.e. superoxide dismutase (SOD) activity and glutathione (GSH) and Heme-oxygenase (HO-1) levels] (2) [58, 84, 129, 130, 137]. Activation of PI3K/Akt, PKC and MAPK/ERK by guanosine leads to stimulation of glutamate transporters activity (3) [124-126]. Guanosine recovers glutamate transporters functionality and increases glutamine synthetase (GS) activity, thus reducing extracellular levels of glutamate and protecting from glutamate excitotoxicity (4) [152]. The inhibition of calcium-dependent (big) conductance potassium (BK) channels and activation of A2AR inhibits guanosine-induced increase in glutamate uptake (5) [124]. Guanosine promotes cell viability recovery by modulation of BK channels, A1R and A2AR [121, 124, 129]. A specific binding site for guanosine was identified as a putative GPCR (or GPR23), but this “guanosine receptor” (GuoR) was not yet fully characterized and its involvement in the neuroprotective effects of guanosine was not evaluated (6) [149, 150]. Figure designed using images from www.servier.com/Powerpoint-image-bank.
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F2-ad-7-5-657: Overview of the main mechanisms involved in the neuroprotective effects of guanosine. Guanosine promotes neuroprotection through reduction of reactive oxygen species levels (ROS) by inhibition of nuclear factor kappa B (NF-κB) activation via MAPK/ERK and by preventing iNOS induction (1) [124]. Guanosine also counteracts ROS production by increasing antioxidant defenses [i.e. superoxide dismutase (SOD) activity and glutathione (GSH) and Heme-oxygenase (HO-1) levels] (2) [58, 84, 129, 130, 137]. Activation of PI3K/Akt, PKC and MAPK/ERK by guanosine leads to stimulation of glutamate transporters activity (3) [124-126]. Guanosine recovers glutamate transporters functionality and increases glutamine synthetase (GS) activity, thus reducing extracellular levels of glutamate and protecting from glutamate excitotoxicity (4) [152]. The inhibition of calcium-dependent (big) conductance potassium (BK) channels and activation of A2AR inhibits guanosine-induced increase in glutamate uptake (5) [124]. Guanosine promotes cell viability recovery by modulation of BK channels, A1R and A2AR [121, 124, 129]. A specific binding site for guanosine was identified as a putative GPCR (or GPR23), but this “guanosine receptor” (GuoR) was not yet fully characterized and its involvement in the neuroprotective effects of guanosine was not evaluated (6) [149, 150]. Figure designed using images from www.servier.com/Powerpoint-image-bank.

Mentions: As discussed above, guanosine displays protective role in in vitro protocols of glutamate challenge, mitochondrial stress, models of ischemia, Parkinson’s and Alzheimer’s diseases and neuroinflammation. From these studies can be stated that the mechanism of guanosine protection against neurodegeneration are related to its ability of modulating the glutamate transport, counteracting oxidative stress, preventing inflammatory damage, thus culminating in prevention from apoptosis. Fig. 2 presents evidence of neuroprotective mechanisms mediated by guanosine.


Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders
Overview of the main mechanisms involved in the neuroprotective effects of guanosine. Guanosine promotes neuroprotection through reduction of reactive oxygen species levels (ROS) by inhibition of nuclear factor kappa B (NF-κB) activation via MAPK/ERK and by preventing iNOS induction (1) [124]. Guanosine also counteracts ROS production by increasing antioxidant defenses [i.e. superoxide dismutase (SOD) activity and glutathione (GSH) and Heme-oxygenase (HO-1) levels] (2) [58, 84, 129, 130, 137]. Activation of PI3K/Akt, PKC and MAPK/ERK by guanosine leads to stimulation of glutamate transporters activity (3) [124-126]. Guanosine recovers glutamate transporters functionality and increases glutamine synthetase (GS) activity, thus reducing extracellular levels of glutamate and protecting from glutamate excitotoxicity (4) [152]. The inhibition of calcium-dependent (big) conductance potassium (BK) channels and activation of A2AR inhibits guanosine-induced increase in glutamate uptake (5) [124]. Guanosine promotes cell viability recovery by modulation of BK channels, A1R and A2AR [121, 124, 129]. A specific binding site for guanosine was identified as a putative GPCR (or GPR23), but this “guanosine receptor” (GuoR) was not yet fully characterized and its involvement in the neuroprotective effects of guanosine was not evaluated (6) [149, 150]. Figure designed using images from www.servier.com/Powerpoint-image-bank.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036959&req=5

F2-ad-7-5-657: Overview of the main mechanisms involved in the neuroprotective effects of guanosine. Guanosine promotes neuroprotection through reduction of reactive oxygen species levels (ROS) by inhibition of nuclear factor kappa B (NF-κB) activation via MAPK/ERK and by preventing iNOS induction (1) [124]. Guanosine also counteracts ROS production by increasing antioxidant defenses [i.e. superoxide dismutase (SOD) activity and glutathione (GSH) and Heme-oxygenase (HO-1) levels] (2) [58, 84, 129, 130, 137]. Activation of PI3K/Akt, PKC and MAPK/ERK by guanosine leads to stimulation of glutamate transporters activity (3) [124-126]. Guanosine recovers glutamate transporters functionality and increases glutamine synthetase (GS) activity, thus reducing extracellular levels of glutamate and protecting from glutamate excitotoxicity (4) [152]. The inhibition of calcium-dependent (big) conductance potassium (BK) channels and activation of A2AR inhibits guanosine-induced increase in glutamate uptake (5) [124]. Guanosine promotes cell viability recovery by modulation of BK channels, A1R and A2AR [121, 124, 129]. A specific binding site for guanosine was identified as a putative GPCR (or GPR23), but this “guanosine receptor” (GuoR) was not yet fully characterized and its involvement in the neuroprotective effects of guanosine was not evaluated (6) [149, 150]. Figure designed using images from www.servier.com/Powerpoint-image-bank.
Mentions: As discussed above, guanosine displays protective role in in vitro protocols of glutamate challenge, mitochondrial stress, models of ischemia, Parkinson’s and Alzheimer’s diseases and neuroinflammation. From these studies can be stated that the mechanism of guanosine protection against neurodegeneration are related to its ability of modulating the glutamate transport, counteracting oxidative stress, preventing inflammatory damage, thus culminating in prevention from apoptosis. Fig. 2 presents evidence of neuroprotective mechanisms mediated by guanosine.

View Article: PubMed Central - PubMed

ABSTRACT

Guanosine is a purine nucleoside with important functions in cell metabolism and a protective role in response to degenerative diseases or injury. The past decade has seen major advances in identifying the modulatory role of extracellular action of guanosine in the central nervous system (CNS). Evidence from rodent and cell models show a number of neurotrophic and neuroprotective effects of guanosine preventing deleterious consequences of seizures, spinal cord injury, pain, mood disorders and aging-related diseases, such as ischemia, Parkinson’s and Alzheimer’s diseases. The present review describes the findings of in vivo and in vitro studies and offers an update of guanosine effects in the CNS. We address the protein targets for guanosine action and its interaction with glutamatergic and adenosinergic systems and with calcium-activated potassium channels. We also discuss the intracellular mechanisms modulated by guanosine preventing oxidative damage, mitochondrial dysfunction, inflammatory burden and modulation of glutamate transport. New and exciting avenues for future investigation into the protective effects of guanosine include characterization of a selective guanosine receptor. A better understanding of the neuromodulatory action of guanosine will allow the development of therapeutic approach to brain diseases.

No MeSH data available.