title: Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions.
abstract: Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 μM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti-inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A1 receptor, phosphatidylinositol-3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin-sensitive G-protein-coupled signaling, blockade of adenosine A2A receptors (A2A R), but not via A1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Tharine
authors.initials: T
authors.lastname: Dal-Cim
authors.forename: Fabiana K
authors.initials: FK
authors.lastname: Ludka
authors.forename: Wagner C
authors.initials: WC
authors.lastname: Martins
authors.forename: Charlise
authors.initials: C
authors.lastname: Reginato
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Carla I
authors.initials: CI
authors.lastname: Tasca
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D018698:Glutamic Acid / Q000493:pharmacokinetics; D006151:Guanosine / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D050857:Synaptotagmins; D014316:Tritium
chemical_list: D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D043682:Receptor, Adenosine A1; C409229:Syt17 protein, rat; D014316:Tritium; D006151:Guanosine; D050857:Synaptotagmins; D018698:Glutamic Acid; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005947:Glucose; D010100:Oxygen
keywords: adenosine receptors; glutamate uptake; guanosine; hippocampal slices; mitogen-activated protein kinases signaling; oxygen/glucose deprivation and reoxygenation