Signaling Mechanisms Underlying the Glioprotective Effects of Guanosine Against Glucose Deprivation-Induced Glial Dysfunction.

Glucose is a critical energy substrate for brain function; therefore, hypoglycemia or compromised glucose metabolism can lead to cognitive impairment and an increased risk for neurodegenerative and neuropsychiatric disorders. Astrocytes are glial cells that act as key regulators of brain glucose metabolism, thus representing important cellular targets for neuroprotection during glucose deprivation. Guanosine, a guanine-based purine, has shown neuroprotective properties in various central nervous system (CNS) disorders. As such, this study aimed to evaluate the potential glioprotective effects of guanosine in a glucose deprivation model, using C6 astroglial cells and focusing on redox imbalance, inflammatory and trophic responses, as well as putative signaling mechanisms associated with these effects. C6 astroglial cells were cultured under normal glucose conditions and subjected to glucose deprivation (culture medium without glucose), with or without guanosine (100 µM) for 12 h. Cytokine levels, oxidative stress markers, mitochondrial function, and NFκB, Nrf2/HO-1, and PI3K/Akt signaling were assessed via ELISA, RT-PCR, colorimetric and fluorescence assays. Glucose deprivation induced glial dysfunction, particularly changes in inflammatory response, redox homeostasis, and cytoprotective/survival signaling pathways. Guanosine prevented glucose deprivation-induced NFκB activation, reducing inflammatory markers (e.g., TNF-α, IL-1β) and restoring S100B secretion. Guanosine also upregulated Nrf2/HO-1 expression, improved antioxidant enzyme activities, mitigated oxidative stress, and preserved mitochondrial membrane potential. Additionally, guanosine restored PI3K/Akt expression and modulated glial-derived factors, including GDNF and TGF-β. By modulating the NFκB, Nrf2/HO-1, and PI3K/Akt pathways, guanosine offers a promising glioprotective strategy to mitigate astrocytic damage during hypoglycemia, potentially reducing CNS injury and associated neurodegeneration.