Guanosine-Mediated Anxiolytic-Like Effect: Interplay with Adenosine A1 and A2A Receptors

Abstract

Acute or chronic administration of guanosine (GUO) induces anxiolytic-like effects, for which the adenosine (ADO) system involvement has been postulated yet without a direct experimental evidence. Thus, we aimed to investigate whether adenosine receptors (ARs) are involved in the GUO-mediated anxiolytic-like effect, evaluated by three anxiety-related paradigms in rats. First, we confirmed that acute treatment with GUO exerts an anxiolytic-like effect. Subsequently, we investigated the effects of pretreatment with ADO or A1R (CPA, CCPA) or A2AR (CGS21680) agonists 10 min prior to GUO on a GUO-induced anxiolytic-like effect. All the combined treatments blocked the GUO anxiolytic-like effect, whereas when administered alone, each compound was ineffective as compared to the control group. Interestingly, the pretreatment with nonselective antagonist caffeine or selective A1R (DPCPX) or A2AR (ZM241385) antagonists did not modify the GUO-induced anxiolytic-like effect. Finally, binding assay performed in hippocampal membranes showed that [3H]GUO binding became saturable at 100–300 nM, suggesting the existence of a putative GUO binding site. In competition experiments, ADO showed a potency order similar to GUO in displacing [3H]GUO binding, whereas AR selective agonists, CPA and CGS21680, partially displaced [3H]GUO binding, but the sum of the two effects was able to displace [3H]GUO binding to the same extent of ADO alone. Overall, our results strengthen previous data supporting GUO-mediated anxiolytic-like effects, add new evidence that these effects are blocked by A1R and A2AR agonists and pave, although they do not elucidate the mechanism of GUO and ADO receptor interaction, for a better characterization of GUO binding sites in ARs.

Raising the Guanosine-Based Molecules as Regulators of Excitable Tissues by the Exosomal-Vehiculated Signaling

“…So, despite the general idea that Guo-stuffed exosomes are released for the endocrine purpose has to be confirmed, it seems fairly possible. Recently, several studies have reported the involvement of Guo-mediated signaling in behavioral outcomes, such as neuroprotection, and anxiolytic-like and analgesic effects (Almeida et al, 2017;Frinchi et al, 2020).…”

Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

“…This is contrary to the results of Dal-Cim et al, who indicate that some neuroprotective effects may be conducted via A 2A R but not A 1 R [68]. Some studies suggest that it is the interplay between coexpressed receptors and the fine-tuning mechanism that are responsible for the neuroprotective effect [64,69].…”

Unfolding New Roles for Guanine-Based Purines and Their Metabolizing Enzymes in Cancer and Aging Disorders

“…Indeed, there is a general consensus about GBPs behaving as a repair system upon brain injury in both in vitro and in vivo models (Lanznaster et al, 2016;Ribeiro et al, 2016). Accordingly, 1) higher extracellular levels of GBPs but not ABPs are detected in cultured astrocytes upon hypoxic or hypoglycaemic conditions (Ciccarelli et al, 1999) ii) GBPs, especially GUO, interferes with glutamatergic system by preventing glutamate excitotoxicity (Tasca et al, 2004;Lanznaster et al, 2017); iii) GBPs demonstrate anxiolytic, antidepressant and anticonvulsant effects (Tavares et al, 2008;Kovacs et al, 2015;Bettio et al, 2016;Frinchi et al, 2020); iv) GUO administration prevents NMDA-evoked neurotoxicity and apoptosis in hippocampal slices (Molz et al, 2008), inhibits the neurotoxin 6hydroxydopamine (6-OHDA)-mediated apoptosis in a model of Parkinson's disease (Giuliani et al, 2012b), induces neuroprotection in hippocampal slices subjected to oxygen/ glucose deprivation (OGD) and ischemia (Ganzella et al, 2012;Dal-Cim et al, 2013); v) GUO stimulates neural stem cells and astrocyte proliferation (Ciccarelli et al, 2000;Su et al, 2013), as well as neurogenesis (Bau et al, 2005;Decker et al, 2007;Piermartiri et al, 2020); vi) GTP induces differentiation of C2C12 skeletal muscle cells and PC12 cells via Ca 2+ -activated K + channel, upon phospholipase C (PLC)/ inositol triphosphate (IP3)/diacylglycerol (DAG) activation (Gysbers and Rathbone, 1996;Guarnieri, Fanò et al, 2004;Pietrangelo, Fioretti et al, 2006;Mancinelli, Pietrangelo et al, 2012) vii) GUA improves learning and memory formation (Giuliani et al, 2012a;Zuccarini et al, 2018b).…”