Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 61, Issue 3, Pages 397-404Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2012.05.021
Keywords
Guanosine; Neuroprotection; Reactive oxygen species; Akt phosphorylation; Heme oxygenase-1
Categories
Funding
- Spanish Ministry of Science and Innovation [SAF2009-12150]
- Ministry of Education [PBH2007-0004-PC]
- Spanish Ministry of Health (Instituto de Salud Carlos III) [RETICS-RD06/0026]
- CAPES (Conselho de Aperfeicoamento de Pessoal de Nivel Superior)
- CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)
- FINEP (Financiadora de Estudos e Projetos - IBN-Net) [01.06.0842-00]
- CAPES/DGU [173/2008]
- CNPq
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Mitochondrial perturbation and oxidative stress are key factors in neuronal vulnerability in several neurodegenerative diseases or during brain ischemia. Here we have investigated the protective mechanism of action of guanosine, the guanine nucleoside, in a human neuroblastoma cell line, SH-SY5Y, subjected to mitochondrial oxidative stress. Blockade of mitochondrial complexes land V with rotenone plus oligomycin (Rot/oligo) caused a significant decrease in cell viability and an increase in ROS production. Guanosine that the protective effect of guanosine incubated concomitantly with Rot/oligo abolished Rot/oligo-induced cell death and ROS production in a concentration dependent manner: maximum protection was achieved at the concentration of 1 mM. The cytoprotective effect afforded by guanosine was abolished by adenosine A(1) or A(2A) receptor antagonists (DPCPX or ZM241385, respectively), or by a large (big) conductance Ca2+-activated K+ channel (BK) blocker (charybdotoxin). Evaluation of signaling pathways showed that the protective effect of guanosine was not abolished by a MEK inhibitor (PD98059), by a p38(MAPK) inhibitor (SB203580), or by a PKC inhibitor (cheleritrine). However, when blocking the PI3K/Akt pathway with LY294002, the neuroprotective effect of guanosine was abolished. Guanosine increased Akt and p-Ser-9-GSK-30 phosphorylation confirming this pathway plays a key role in guanosine's neuroprotective effect. Guanosine induced the antioxidant enzyme heme oxygenase-1 (HO-1) expression. The protective effects of guanosine were prevented by heme oxygenase-1 inhibitor, SnPP. Moreover, bilirubin, an antioxidant and physiologic product of HO-1, is protective against mitochondrial oxidative stress. In conclusion, our results show that guanosine can afford protection against mitochondrial oxidative stress by a signaling pathway that implicates Pl3K/Akt/GSK-3 beta proteins and induction of the antioxidant enzyme HO-1. (C) 2012 Elsevier Ltd. All rights reserved.
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