title: 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 azide-induced 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 highlight the potential role of guanosine against neuroinflammatory-related diseases.
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil. brunabellaver90@gmail.com.
authors.forename: Bruna
authors.initials: B
authors.lastname: Bellaver
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Débora Guerini
authors.initials: DG
authors.lastname: Souza
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Larissa Daniele
authors.initials: LD
authors.lastname: Bobermin
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Carlos-Alberto
authors.initials: CA
authors.lastname: Gonçalves
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Diogo Onofre
authors.initials: DO
authors.lastname: Souza
authors.affiliation: Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Quincozes-Santos
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D006151:Guanosine / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000187:drug effects*; D006624:Hippocampus / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D015398:Signal Transduction
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D006151:Guanosine; D051547:Heme Oxygenase-1
keywords: Astrocytes; Glioprotection; Guanosine; HO-1; NFκB; Neuroinflammation