Purine nucleosides protect injured neurons and stimulate neuronal regeneration by intracellular and membrane receptor‐mediated mechanisms

Abstract

Like adenine-based purines, extracellular nonadenine-based purines have a multitude of trophic effects on the growth, differentiation, and survival of target cells. The nonadenine-based purines, which include guanosine, inosine, and GTP, apparently exert their trophic effects by interacting with both intercellular targets as well as those on the cell surface. Specifically, guanosine and inosine target the protein kinase N-kinase, in promoting remarkable nerve process extension, even in long tracts of the central nervous system after injury. In contrast, GTP may exert its effects via a cell surface receptor coupled to the release of calcium from internal stores. In other cases trophic effects may be mediated by the enhancement of release of adenine-based purines by guanosine. Additionally, evidence is presented for the existence of a high-affinity binding site for guanosine with receptor-like characteristics on the plasma membranes of astrocytes and brain tissue. This site may be G-protein-coupled and exert its effects through activation of the MAP kinase cascade. One effect apparently mediated through this mechanism is the production and release by astrocytes of trophic protein growth factors such as NGF and TGFβ. These have substantial neuroprotective effects. Additionally, this pathway is apparently involved in modulating the expression of P2Y 1 and P2Y 2 receptors in response to extracellular guanosine. Extracellular nonadenine-based purines can interact with other growth factors, but these interactions are not always synergistic. For example, combinations of guanosine and FGF are antagonistic and reduce the growth of microvascular cells in vitro. Some of the properties of the nonadenine-based purines likely derive from their unique intracellular metabolism in which conversion of guanine to xanthine is the final catabolic step. This step is catalyzed by guanase, the activity of which varies markedly in different brain regions, raising the possibility that guanine or guanosine are involved in neurotransmission. Together these data suggest several potentially useful pharmacological approaches involving nonadenine-based purines to modulate trophic effects in the central nervous system. Drug Dev. Res. 52:303-315, 2001.

Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and β Amyloid in Mouse Microglia Cells

“…However, the mechanism underlying this effect is not linked to the inhibition of TNF-␣-induced IB␣ phosphorylation/degradation, as we reported for guanosine here (52). Because PTX prevents the inhibition by guanosine on cytokine-induced CD40 expression, we speculate that guanosine exerts a part of its activity by interacting with G i protein-linked receptors, which might correspond to the specific binding sites, the existence of which we demonstrated in membranes deriving from rat whole brain and astrocytes (41,67). Of course, specific receptor cloning or availability of selective antagonists for guanosine will allow to demonstrate this aspect.…”

“…However, we have previously reported that guanosine increases the extracellular concentration of adenosine and adenine-based nucleotides, at least in cultured astrocytes (37,41,48). Because purines and adenosine, in particular, are considered endogenous immunomodulators, able to affect the signaling of inflammatory cytokines, including TNF-␣, in different cell types (52), we wanted to ascertain whether the inhibitory effect of guanosine on cytokine-induced CD40 expression was due to adenosine or ATP.…”

“…Guanosine exhibits antiinflammatory and immunosuppressive properties (35,36) and exerts a number of neurotrophic and neuroprotective effects, including astrocyte proliferation (37,38), promotion of neurite outgrowth (39), increased synthesis, and release of neuro/pleiotrophins such as nerve growth factor, TGF-␤ and basic fibroblast growth factor, from several cell types (40,41), and enhanced glutamate uptake by astrocytes (42). Recently, we demonstrated that guanosine protects astrocytes against apoptotic death caused by staurosporine (43) and SH-SY5Y human neuroblastoma cells against apoptosis induced by A␤ peptides (44).…”

Guanosine and its role in neuropathologies

“…However, it should be noted that many of the effects of guanosine persist in the presence of P1 antagonists [43], indicating that this nucleoside also acts by distinct mechanisms that are independent of the adenosinergic system. Within this context, it has been proposed that the biological activity of guanosine may be mediated, at least in part, by its own specific receptors [15,39,82,86]. Indeed, a G-protein-coupled site seems to be important for the neuroprotective effects of this nucleoside, namely, during the guanosine-induced stimulation of glutamate uptake and the release of trophic factors by astrocytes [39,82,86].…”

“…These actions seem to be mediated by the ability of this nucleoside to stimulate the astrocytic release of several endogenous regulators of survival, proliferation, and differentiation, including trophic factors such as nerve growth factor (NGF), transforming growth factor beta (TGFβ), and fibroblast growth factor 2 (FGF-2) [15,[37][38][39]. In addition, the release of these factors by guanosine may be related to the modulatory effects that this molecule has on astrocytic activity.…”