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.

Guanosine prevents nitroxidative stress and recovers mitochondrial membrane potential disruption in hippocampal slices subjected to oxygen/glucose deprivation

“…Here, we confirm and extend the knowledge related to the mechanisms involved in the neuroprotective effects of guanosine (GUO) in neurotoxicity and neurodegenerative rodent models [5,12,33,[37][38][39]. In previous studies from our group, the neuroprotective effect of GUO was shown in hippocampal slices subjected to the OGD/reoxygenation protocol.…”

“…Moreover, GUO is effective in reducing ROS production, iNOS expression and NF-kB activation, and preventing the loss of mitochondrial membrane potential. Additionally, it decreased cells membrane permeability and glutamate release, and recovered glutamine synthetase activity in slices subjected to OGD [12,15].…”

“…An endogenous neuroprotective agent that had been considered as a putative anti-ischemic strategy is guanosine (GUO), the guanine-derived nucleoside. GUO presents neuroprotective effect in in vivo and in vitro experimental models of brain diseases associated with glutamatergic excitotoxicity [11,12]. It was showed that after focal stroke in rats, GUO levels are elevated within 2 h and remain high for 7 days in the brain tissue [13].…”

Guanosine promotes cytotoxicity via adenosine receptors and induces apoptosis in temozolomide-treated A172 glioma cells

“…Guanosine (GUO) is an endogenous guanine-derived nucleoside involved in extracellular signaling that presents the ability to modulate glutamatergic system activity [11,12]. In this regard, GUO exerts neuroprotective effects against glutamate-induced cell damage or ischemia, through activation of intracellular signaling pathways related to cell survival as the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) [13,14].…”

“…GUO also modulates glutamate transporter activity, by preventing the decrease in glutamate uptake and the increased glutamate release on in vitro models of ischemia [14][15][16][17]. A selective receptorial protein to GUO has been suggested, although it has not yet been cloned (for a review see [12]). However, the neuroprotective effect of GUO seems to involve the modulation of adenosine receptors (AdoR) [14] and/or the activation of the large (big) conductance Ca 2+ -activated K + channels (BK) [15].…”