Central nervous system (CNS) astrocytes release guanosine extracellularly, that exerts trophic effects. In CNS, extracellular guanosine (GUO) stimulates mitosis, synthesis of trophic factors, and cell differentiation, including neuritogenesis, is neuroprotective, and reduces apoptosis due to several stimuli. Specific receptor-like binding sites for eGUO in the nervous system may mediate its effects through both MAP kinase and PI3-kinase signalling pathways. Extracellular guanine (eGUA) also exerts several effects; the trophic effects of eGUO are likely regulated by conversion of eGUO to eGUA by a membrane located purine nucleoside phosphorylase (ecto-PNP) and by conversion of eGUA to xanthine by guanine deaminase.

Mild traumatic brain injuries (mTBIs) trigger a neuroinflammatory response, which leads to perturbations in the levels of inflammatory cytokines, resulting in a distinctive profile. A systematic review and meta-analysis were conducted to synthesize data related to levels of inflammatory cytokines in patients with mTBI. The electronic databases EMBASE, MEDLINE, and PUBMED were searched from January 2014 to December 12, 2021. A total of 5,138 articles were screened using a systematic approach based on the PRISMA and R-AMSTAR guidelines. Of these articles, 174 were selected for full-text review and 26 were included in the final analysis. The results of this study demonstrate that within 24 hours, patients with mTBI have significantly higher levels of Interleukin-6 (IL-6), Interleukin-1 Receptor Antagonist (IL-1RA), and Interferon-γ (IFN-γ) in blood, compared to healthy controls in majority of the included studies. Similarly one week following the injury, patients with mTBI have higher circulatory levels of Monocyte Chemoattractant Protein-1/C-C Motif Chemokine Ligand 2 (MCP-1/CCL2), compared to healthy controls in majority of the included studies. The results of the meta-analysis also confirmed these findings by demonstrating significantly elevated blood levels of IL-6, MCP-1/CCL2, and Interleukin-1 beta (IL-1β) in the mTBI population compared to healthy controls (p < 0.0001), particularly in the acute stages (<7 days). Furthermore, it was found that IL-6, Tumor Necrosis Factor-alpha (TNF-α), IL-1RA, IL-10, and MCP-1/CCL2 were associated with poor clinical outcomes following the mTBI. Finally, this research highlights the lack of consensus in the methodology of mTBI studies that measure inflammatory cytokines in the blood, and also provides direction for future mTBI research.

Undifferentiated rat pheochromocytoma (PC12) cells extend neurites when cultured in the presence of nerve growth factor (NGF). Extracellular guanosine synergistically enhances NGF-dependent neurite outgrowth. We investigated the mechanism by which guanosine enhances NGF-dependent neurite outgrowth. Guanosine administration to PC12 cells significantly increased guanosine 3-5-cyclic monophosphate (cGMP) within the first 24 h whereas addition of soluble guanylate cyclase (sGC) inhibitors abolished guanosine-induced enhancement of NGF-dependent neurite outgrowth. sGC may be activated either by nitric oxide (NO) or by carbon monoxide (CO). \(N^{\omega } \)-Nitro-l-arginine methyl ester (l-NAME), a non-isozyme selective inhibitor of nitric oxide synthase (NOS), had no effect on neurite outgrowth induced by guanosine. Neither nNOS (the constitutive isoform), nor iNOS (the inducible isoform) were expressed in undifferentiated PC12 cells, or under these treatment conditions. These data imply that NO does not mediate the neuritogenic effect of guanosine. Zinc protoporphyrin-IX, an inhibitor of heme oxygenase (HO), reduced guanosine-dependent neurite outgrowth but did not attenuate the effect of NGF. The addition of guanosine plus NGF significantly increased the expression of HO-1, the inducible isozyme of HO, after 12 h. These data demonstrate that guanosine enhances NGF-dependent neurite outgrowth by first activating the constitutive isozyme HO-2, and then by inducing the expression of HO-1, the enzymes responsible for CO synthesis, thus stimulating sGC and increasing intracellular cGMP.

Guanosine exerts neuroprotective effects in the central nervous system. Apoptosis, a morphological form of programmed cell death, is implicated in the pathophysiology of Parkinson’s disease (PD). MPP⁺, a dopaminergic neurotoxin, produces in vivo and in vitro cellular changes characteristic of PD, such as cytotoxicity, resulting in apoptosis. Undifferentiated human SH-SY5Y neuroblastoma cells had been used as an in vitro model of Parkinson’s disease. We investigated if extracellular guanosine affected MPP⁺-induced cytotoxicity and examined the molecular mechanisms mediating its effects. Exposure of neuroblastoma cells to MPP⁺ (10 μM–5 mM for 24–72 h) induced DNA fragmentation in a time-dependent manner (p < 0.05). Administration of guanosine (100 μM) before, concomitantly with or, importantly, after the addition of MPP⁺ abolished MPP⁺-induced DNA fragmentation. Addition of MPP⁺ (500 μM) to cells increased caspase-3 activity over 72 h (p < 0.05), and this was abolished by pre- or co-treatment with guanosine. Exposure of cells to pertussis toxin prior to MPP⁺ eliminated the anti-apoptotic effect of guanosine, indicating that this effect is dependent on a Gi protein-coupled receptor, most likely the putative guanosine receptor. The protection by guanosine was also abolished by the selective inhibitor of the enzyme PI-3-K/Akt/PKB (LY294002), confirming that this pathway plays a decisive role in this effect of guanosine. Neither MPP⁺ nor guanosine had any significant effect on α-synuclein expression. Thus, guanosine antagonizes and reverses MPP⁺-induced cytotoxicity of neuroblastoma cells via activation of the cell survival pathway, PI-3-K/Akt/PKB. Our results suggest that guanosine may be an effective pharmacological intervention in PD.

Both mild traumatic brain injuries (mTBI) and systemic injuries trigger a transient neuroinflammatory response that result in similar clinical outcome. The ensuing physical, cognitive, and emotional symptoms fail to subside in approximately 15–20% of the concussed population. Emotional impairments, particularly depression, anxiety, and post-traumatic stress disorder (PTSD), are commonly associated with poor recovery following mTBI. These emotional impairments also have a significant neuroinflammatory component. We hypothesized that the inflammatory cytokines seen in mTBI patients with emotional symptoms would coincide with those commonly seen in patients with emotional symptoms without mTBI. A systematic review was conducted to identify the most common neuroinflammatory cytokines in the mTBI population with psychological symptoms (depression, anxiety, PTSD). The electronic databases EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, and PSYCINFO were searched from data inception to 31 August 2021. A systematic screening approach was employed from screening to data analysis. A total of 994 articles were screened, 108 were selected for full article review, and 8 were selected for data analysis. The included studies consisted of 875 patients of which 81.3% were male. The mean sample size of patients with at least one mTBI was 73.8 ± 70.3 (range, 9–213), with a mean age of 33.9 ± 4.8 years. The most common cytokines associated with poor psychological outcomes involving PTSD and/or depression in the chronic mTBI population were IL-6, TNFα, IL-10, and CRP.