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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.


Related in: MedlinePlus

Guanine-based purines catabolism. GTP, GDP and GMP are hydrolyzed sequentially by nucleotidases (or ecto-nucleotidases, when produced extracellularly), generating guanosine (GUO). Ecto-NTPDase (or apyrase) metabolizes GTP and GDP to produce GMP. Guanosine is hydrolyzed by PNP generating the purine base guanine (GUA). By action of a guanine deaminase, guanine is converted to xanthine and sequentially to uric acid by action of a xanthine oxidase. The salvage purines pathway enzyme HGPRT produces GMP or IMP from condensation of GUA or hypoxanthine with 5’-phosphoribosyl, respectively (blue arrows). Ecto-NTPDase, ecto-nucleotide diphosphohydrolase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PNP, purine nucleoside phosphorylase.
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F1-ad-7-5-657: Guanine-based purines catabolism. GTP, GDP and GMP are hydrolyzed sequentially by nucleotidases (or ecto-nucleotidases, when produced extracellularly), generating guanosine (GUO). Ecto-NTPDase (or apyrase) metabolizes GTP and GDP to produce GMP. Guanosine is hydrolyzed by PNP generating the purine base guanine (GUA). By action of a guanine deaminase, guanine is converted to xanthine and sequentially to uric acid by action of a xanthine oxidase. The salvage purines pathway enzyme HGPRT produces GMP or IMP from condensation of GUA or hypoxanthine with 5’-phosphoribosyl, respectively (blue arrows). Ecto-NTPDase, ecto-nucleotide diphosphohydrolase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PNP, purine nucleoside phosphorylase.

Mentions: Extracellular nucleotides are hydrolyzed by a family of ecto-nucleotidases associated to the cell surface, the ecto-nucleoside triphosphate (ecto-NTPase) family [44]. The ecto-NTPases include the ecto-ATPase that hydrolyses ATP and GTP (and also pyrimidine nucleotides with less affinity) to ADP and GDP; the ecto-ATP-diphosphohydrolase or apyrase (ecto-NTPDase), that hydrolyses either ATP or GTP and ADP or GDP to AMP or GMP [45]; and the ecto-5’-nucleotidase that hydrolyses AMP or GMP to the nucleosides adenosine and guanosine [46] (Fig. 1). Thus, after brain injury, released nucleotides undergo hydrolysis and their respective nucleosides may display a protective effect. In addition to this evidence of guanine derivatives being released in pathological situations, our group showed that GTP is taken up and stored into brain synaptic vesicles, suggesting that this nucleotide may act as a neurotransmitter [47].


Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders
Guanine-based purines catabolism. GTP, GDP and GMP are hydrolyzed sequentially by nucleotidases (or ecto-nucleotidases, when produced extracellularly), generating guanosine (GUO). Ecto-NTPDase (or apyrase) metabolizes GTP and GDP to produce GMP. Guanosine is hydrolyzed by PNP generating the purine base guanine (GUA). By action of a guanine deaminase, guanine is converted to xanthine and sequentially to uric acid by action of a xanthine oxidase. The salvage purines pathway enzyme HGPRT produces GMP or IMP from condensation of GUA or hypoxanthine with 5’-phosphoribosyl, respectively (blue arrows). Ecto-NTPDase, ecto-nucleotide diphosphohydrolase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PNP, purine nucleoside phosphorylase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

F1-ad-7-5-657: Guanine-based purines catabolism. GTP, GDP and GMP are hydrolyzed sequentially by nucleotidases (or ecto-nucleotidases, when produced extracellularly), generating guanosine (GUO). Ecto-NTPDase (or apyrase) metabolizes GTP and GDP to produce GMP. Guanosine is hydrolyzed by PNP generating the purine base guanine (GUA). By action of a guanine deaminase, guanine is converted to xanthine and sequentially to uric acid by action of a xanthine oxidase. The salvage purines pathway enzyme HGPRT produces GMP or IMP from condensation of GUA or hypoxanthine with 5’-phosphoribosyl, respectively (blue arrows). Ecto-NTPDase, ecto-nucleotide diphosphohydrolase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PNP, purine nucleoside phosphorylase.
Mentions: Extracellular nucleotides are hydrolyzed by a family of ecto-nucleotidases associated to the cell surface, the ecto-nucleoside triphosphate (ecto-NTPase) family [44]. The ecto-NTPases include the ecto-ATPase that hydrolyses ATP and GTP (and also pyrimidine nucleotides with less affinity) to ADP and GDP; the ecto-ATP-diphosphohydrolase or apyrase (ecto-NTPDase), that hydrolyses either ATP or GTP and ADP or GDP to AMP or GMP [45]; and the ecto-5’-nucleotidase that hydrolyses AMP or GMP to the nucleosides adenosine and guanosine [46] (Fig. 1). Thus, after brain injury, released nucleotides undergo hydrolysis and their respective nucleosides may display a protective effect. In addition to this evidence of guanine derivatives being released in pathological situations, our group showed that GTP is taken up and stored into brain synaptic vesicles, suggesting that this nucleotide may act as a neurotransmitter [47].

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.


Related in: MedlinePlus