Current perspectives on the antidepressant-like effects of guanosine

Purines have a recognized importance as intercellular messengers. These molecules play an important role in the development and maintenance of the central nervous system (CNS), as well as in its response to pathological conditions. Both adenine and guanine-based purines can be released from astrocytes, where they play a relevant role as extracellular signaling molecules. Particularly, the nucleoside guanosine has been proposed as an extracellular molecule that regulates the response of CNS to damage. Following injury, this nucleoside attains high concentrations in the extracellular space, where it activates multiple signaling pathways, leading to neurotrophic and neuroprotective effects. Despite the fact that the role of guanosine in the CNS is just now being elucidated, several lines of evidence have suggested that this nucleoside protects neural tissue from damage by activating anti-apoptotic, anti-inflammatory and antioxidant mechanisms (Rathbone et al., 2008). Within this context, the protective effects of guanosine have been demonstrated against a plethora of different insults. These effects seem to be partially mediated by a specific G-protein coupled binding site, raising the possibility of existence of a putative guanosine receptor. Additionally, the trophic and neuroprotective effects of guanosine also appear to involve an interaction with the adenosinergic system, since blockage of adenosine A1 and A2A receptors can partially inhibit these pro-survival properties of guanosine (which does not act as a ligand for these receptors). The action of guanosine on both the specific G-protein coupled binding site and the adenosinergic receptors is associated with the activation of pro-survival signaling pathways such as those involving the phosphatidylinositol-3 kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) (Rathbone et al., 2008). Indeed, synchronization of distinct signaling pathways by this nucleoside seems to underlie most of its trophic and neuroprotective properties, including its ability to stimulate astrocytic glutamate uptake and the release of growth factors, as well as the induction of anti-inflammatory and antioxidant responses (Rathbone et al., 2008; Bettio et al., 2016a). The trophic response elicited by guanosine involves the astrocytic release of molecules with a crucial role in the reparative processes of CNS including nerve growth factor (NGF), transforming growth factor beta (TGFβ) and fibroblast growth factor 2 (FGF-2) (Bau et al., 2005; Rathbone et al., 2008; Su et al., 2009). Furthermore, this nucleoside is able to induce neural stem cell proliferation by increasing the expression of brain-derived neurotrophic factor (BDNF) (Su et al., 2013). Keeping in mind that the multiple mechanisms underlying guanosine activity are commonly dysregulated in most neuropathologies (i.e., excitotoxicity, neuroinflammation and oxidative damage), several studies have evaluated the therapeutic potential of this molecule in different in vitro and in vivo models of neurological conditions (for review see Bettio et al., 2016a). Within this context, the idea that guanosine may be an interesting target for future clinical investigations is supported not only by its protective effects, but also by its ability to stimulate regenerative processes in the CNS. For instance, the combination of neuroprotective and trophic properties of guanosine have an impact in the loss of dopaminergic neurons observed in Parkinson’s disease, as evidenced by a study investigating the functional recovery induced by chronic administration of this nucleoside in rats with parkinsonism (Su et al., 2009). This symptomatic improvement was related to the ability of guanosine to reduce apoptosis, stimulate neurogenesis in the subventricular zone (SVZ) and increase the number of tyrosine hydroxylase positive cells in the substantia nigra. Moreover, the relevance of guanosine for neural regeneration is further reinforced by studies investigating its systemic administration in rodents with spinal cord injury (SCI). Similarly, the functional recovery elicited by this nucleoside in SCI models seems to occur both through prevention of damage during the acute phase (i.e., inflammatory cascades and apoptosis) and stimulation of regenerative processes (i.e., proliferation and maturation of progenitor cells involved in remyelination) (Jiang et al., 2008).