Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders

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.

Keywords: adenosine; glutamate; guanosine; neuromodulator; neuroprotection; neurotrophic effects; purines.

Figure 1.

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.

Figure 2.

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 A_2AR inhibits guanosine-induced increase in glutamate uptake (5) [124]. Guanosine promotes cell viability recovery by modulation of BK channels, A₁R and A_2AR [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.

Figure 3.

Schematic illustration of the neurotrophic effects of guanosine. In astrocytes cerebellar cultures guanosine promotes the reorganization of extracellular matrix proteins fibronectin and laminin (photomicrographs from Decker H. and colleagues [145]) via CaMKII, PKA, MAPK/ERK, PKC and PI3K/AKT activation (1) [145]. Guanosine also increases the number of cerebellar neurons in culture (or in coculture with astrocytes) by activation of these kinases. This guanosine neurotrophic effect involves A_2AR activation and it is also dependent on NMDAR and Kainate receptors activation (2) [39]. In neural stem cells guanosine increases intracellular cAMP, CREB phosphorylation and BDNF mRNA levels (3) [62]. Guanosine promotes neurite outgrowth in cerebellar neurons culture by PKC activation (4) [143] and in PC12 by heme-oxygenase (HO-1) induction (5) [144]. In cultured astrocytes, guanosine promotes cellular proliferation (6) [116] and synthesis and release of neurotrophic factors, as FGF-2 and NGF (7) [141]. These neurotrophic effects of guanosine may be involved in cell survival. Figure designed using images from www.servier.com/Powerpoint-image-bank.