Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway

Abstract

Guanosine, a guanine-based purine, is an extracellular signaling molecule that is released from astrocytes and has been shown to promote central nervous system defenses in several in vivo and in vitro injury models. Our group recently demonstrated that guanosine exhibits glioprotective effects in the C6 astroglial cell line by associating the heme oxygenase-1 (HO-1) signaling pathway with protection against azideinduced oxidative stress. Astrocyte overactivation contributes to the triggering of brain inflammation, a condition that is closely related to the development of many neurological disorders. These cells sense and amplify inflammatory signals from microglia and/or initiate the release of inflammatory mediators that are strictly related to transcriptional factors, such as nuclear factor kappa B (NFκB), that are modulated by HO-1. Astrocytes also express toll-like receptors (TLRs); TLRs specifically recognize lipopolysaccharide (LPS), which has been widely used to experimentally study inflammatory response. This study was designed to understand the glioprotective mechanism of guanosine against the inflammatory and oxidative damage induced by LPS exposure in primary cultures of hippocampal astrocytes. Treatment of astrocytes with LPS resulted in deleterious effects, including the augmentation of pro-inflammatory cytokine levels, NFκB activation, mitochondrial dysfunction, increased levels of oxygen/nitrogen species, and decreased levels of antioxidative defenses. Guanosine was able to prevent these effects, protecting the hippocampal astrocytes against LPS-induced cytotoxicity through activation of the HO-1 pathway. Additionally, the anti-inflammatory effects of guanosine were independent of the adenosinergic system. These results highl i g h t t h e p o t e n t i a l r o l e o f g u a n o s i n e a g a i n s t neuroinflammatory-related diseases.

Guanosine and its role in neuropathologies

“…Within this context, it has been shown that this nucleoside is able to prevent the production of reactive oxygen species (ROS) and to counteract alterations in inflammatory parameters, such as an increase in interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) and a decrease in the levels of the antiinflammatory cytokine interleukin 10 (IL-10) [92,93]. Furthermore, the guanosine-induced activation of the PI3K/Akt and MAPKs signaling pathways is also related to the inhibition of nuclear factor-kappaB (NF-κB) and inducible nitric oxide synthase (iNOS) [82,83,94] and with the induction of the expression of hemeoxygenase-1 (HO-1) [53,83,92,94].…”

“…1), it is not surprising that this nucleoside was shown to be neuroprotective both in vitro and in vivo against a plethora of different insults, including excitotoxins [95,96], apoptosis induced by staurosporine [86], stress-induced oxidative damage [97], sepsis-induced cognitive impairment [98], hepatic encephalopathy [99], azide-induced oxidative damage [100], lipopolysaccharide (LPS)-induced inflammation [94], ischemic damage [63,101,102], toxicity induced by amyloid β peptide (Aβ) [91,103] as well as 1-methyl-4-phenylpyridinium (MPP + ) and 6-hydroxydopamine (6-OHDA) [36,[104][105][106], and spinal cord injury (SCI) [107,108]. Based on these studies, the modulation of the purinergic system has emerged as a therapeutic approach for the treatment of various neurological conditions, and guanosine in particular may be a therapeutic target for several of these neuropathologies.…”

“…Moreover, this nucleoside also stimulates the astrocytic release of trophic factors and activates neuroprotective mechanisms including antiapoptotic, antiinflammatory, and antioxidant responses. [94] ↓ Seizures (through a mechanism distinct from that of MK-801) [119] ↓ Oxidative stress; ↑ endogenous antioxidants [87] Stroke (hypoxia/ischemia) In vitro…”

Anti-aging effects of guanosine in glial cells

“…Guanosine, more specifically, has been shown to induce numerous beneficial cellular responses in several brain injuries, such as seizures, hypoxia, anxiety-like behavior, ischemia, and glucose deprivation [1,[6][7][8][9]. In addition to demonstrating the ability to modulate glutamatergic metabolism, avoiding the overactivation of glutamate receptors, and exerting antioxidant and anti-inflammatory activities [10][11][12], guanosine can also modulate several signaling pathways to provide neuroprotection [1,13,14]. However, despite the increasing evidence of the protective effects of guanosine in neural cells, its mechanism of action is not fully understood.…”

“…Our group has previously demonstrated the interplay between guanosine and the enzyme heme oxygenase 1 (HO-1) [12,14], which is the major enzyme responsible for the conversion of heme into CO and the antioxidant products biliverdin and bilirubin [15,16]. It has been reported that HO-1 may be a therapeutic target in the aging process and/or neurodegenerative diseases.…”