Abstract
Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke.
Highlights
Stroke is one of the top causes of death worldwide and the leading cause of permanent disability in developed countries, affecting approximately one in six people in their lifetime worldwide [1,2,3]
Starting from the observations of endogenous guanosine release under ischemia, we explore the concept of the therapeutic potential of exogenous guanosine
We comprehensively summarized the recent advances in the neuroprotective effects of Guo in ischemic stroke
Summary
Stroke is one of the top causes of death worldwide and the leading cause of permanent disability in developed countries, affecting approximately one in six people in their lifetime worldwide [1,2,3]. Guanosine (Guo), a part of a guanine-based purinergic system, emerged as a novel neuroprotectant and neuromodulator in CNS disorders In this comprehensive review, we describe in depth the role and effects of extracellular guanosine in in vitro and in vivo models of ischemic stroke. To the best of our knowledge, there is currently no available experimental data regarding the neuroprotective effects of Guo in hemorrhagic stroke; the scope of the study was limited to ischemic stroke models. GDs induce proliferative effects, emphasized by an increase in the number of neurons, and proliferation markers in both in vitro and in vivo studies [12,24,25,26,27]. The number of neurons in cocultures increased, putatively due to increased neuronal viability or the neuritogenetic properties of laminin [26]
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