Guanosine and its role in neuropathologies

Abstract

Guanosine is a purine nucleoside thought to have neuroprotective properties. It is released in the brain under physiological conditions and even more during pathological events, reducing neuroinflammation, oxidative stress, and excitotoxicity, as well as exerting trophic effects in neuronal and glial cells. In agreement, guanosine was shown to be protective in several in vitro and/or in vivo experimental models of central nervous system (CNS) diseases including ischemic stroke, Alzheimer's disease, Parkinson's disease, spinal cord injury, nociception, and depression. The mechanisms underlying the neurobiological properties of guanosine seem to involve the activation of several intracellular signaling pathways and a close interaction with the adenosinergic system, with a consequent stimulation of neuroprotective and regenerative processes in the CNS. Within this context, the present review will provide an overview of the current literature on the effects of guanosine in the CNS. The elucidation of the complex signaling events underlying the biochemical and cellular effects of this nucleoside may further establish guanosine as a potential therapeutic target for the treatment of several neuropathologies.

Keywords: Guanine-based purines; Guanosine; Neuroprotection; Neurotrophic; Purinergic system.

Fig. 1

Mechanisms underlying the effects of extracellular guanosine. Astrocytes are the main source of guanine-based purines (GBPs) in the central nervous system (CNS). Guanosine present in the extracellular space originates from the catabolism of guanine nucleotides by ecto-nucleotidases, which are increased following injury. It is believed that accumulation of cyclic adenosine monophosphate (cAMP) and activation of phosphatidyl inositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling pathways play a crucial role in the biological activity of this nucleoside. These signaling pathways appear to be related with the activation of a specific G-protein-coupled receptor for guanosine, but its existence is still a matter of debate. Moreover, the activity of P1 receptors also contributes to guanosine effects, although the exact molecular interactions underlying this contribution are currently unknown. At the synaptic level, guanosine stimulates astrocytic glutamate uptake, preventing events linked to excitotoxicity. Moreover, this nucleoside also stimulates the astrocytic release of trophic factors and activates neuroprotective mechanisms including antiapoptotic, antiinflammatory, and antioxidant responses. Figure was produced with permission using Servier Medical Art (www.servier.com)