| Autor: |
Dal-Cim T; Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianopolis, SC, 88040-900, Brazil.; Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil., Poluceno GG; Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianopolis, SC, 88040-900, Brazil.; Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil., Lanznaster D; Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianopolis, SC, 88040-900, Brazil.; Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil., de Oliveira KA; Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianopolis, SC, 88040-900, Brazil.; Programa de Pós-graduação em Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil., Nedel CB; Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil., Tasca CI; Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianopolis, SC, 88040-900, Brazil. carla.tasca@ufsc.br.; Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil. carla.tasca@ufsc.br.; Programa de Pós-graduação em Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil. carla.tasca@ufsc.br. |
| Abstrakt: |
Glial cells are involved in multiple cerebral functions that profoundly influence brain tissue viability during ischemia, and astrocytes are the main source of extracellular purines as adenosine and guanosine. The endogenous guanine-based nucleoside guanosine is a neuromodulator implicated in important processes in the brain, such as modulation of glutamatergic transmission and protection against oxidative and inflammatory damage. We evaluated if the neuroprotective effect of guanosine is also observed in cultured cortical astrocytes subjected to oxygen/glucose deprivation (OGD) and reoxygenation. We also assessed the involvement of A 1 and A 2A adenosine receptors and phosphatidylinositol-3 kinase (PI3K), MAPK, and protein kinase C (PKC) signaling pathways on the guanosine effects. OGD/reoxygenation decreased cell viability and glutamate uptake and increased reactive oxygen species (ROS) production in cultured astrocytes. Guanosine treatment prevented these OGD-induced damaging effects. Dipropyl-cyclopentyl-xanthine (an adenosine A 1 receptor antagonist) and 4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid hydrochloride (an adenosine A 2A receptor agonist) abolished guanosine-induced protective effects on ROS production, glutamate uptake, and cell viability. The PI3K pathway inhibitor 2-morpholin-4-yl-8-phenylchromen-4-one, the extracellular-signal regulated kinase kinase (MEK) inhibitor 2'-amino-3'-methoxyflavone, or the PKC inhibitor chelerythrine abolished the guanosine effect of preventing OGD-induced cells viability reduction. PI3K inhibition partially prevented the guanosine effect of reducing ROS production, whereas MEK and PKC inhibitions prevented the guanosine effect of restoring glutamate uptake. The total immunocontent of the main astrocytic glutamate transporter glutamate transporter-1 (GLT-1) was not altered by OGD and guanosine. However, MEK and PKC inhibitions also abolished the guanosine effect of increasing cell-surface expression of GLT-1 in astrocytes subjected to OGD. Then, guanosine prevents oxidative damage and stimulates astrocytic glutamate uptake during ischemic events via adenosine A 1 and A 2A receptors and modulation of survival signaling pathways, contributing to microenvironment homeostasis that culminates in neuroprotection. |
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