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The antidepressant-like effect of guanosine is dependent on GSK-3β inhibition and activation of MAPK/ERK and Nrf2/heme oxygenase-1 signaling pathways

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Abstract

Although guanosine is an endogenous nucleoside that displays antidepressant-like properties in several animal models, the mechanism underlying its antidepressant-like effects is not well characterized. The present study aimed at investigating the involvement of ERK/GSK-3β and Nrf2/HO-1 signaling pathways in the antidepressant-like effect of guanosine in the mouse tail suspension test (TST). The immobility time in the TST was taken as an indicative of antidepressant-like responses and the locomotor activity was assessed in the open-field test. Biochemical analyses were performed by Western blotting in the hippocampus and prefrontal cortex (PFC). The combined treatment with sub-effective doses of guanosine (0.01 mg/kg, p.o.) and lithium chloride (a non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, 0.01 μg/site, i.c.v.) produced a synergistic antidepressant-like effect in the TST. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) was completely prevented by the treatment with MEK1/2 inhibitors U0126 (5 μg/site, i.c.v.), PD98059 (5 μg/site, i.c.v.), or zinc protoporphyrin IX (ZnPP) (HO-1 inhibitor, 10 μg/site, i.c.v). Guanosine administration (0.05 mg/kg, p.o.) increased the immunocontent of β-catenin in the nuclear fraction and Nrf2 in the cytosolic fraction in the hippocampus and PFC. The immunocontent of HO-1 was also increased in the hippocampus and PFC. Altogether, the results provide evidence that the antidepressant-like effect of guanosine in the TST involves the inhibition of GSK-3β, as well as activation of MAPK/ERK and Nrf2/HO-1 signaling pathways, highlighting the relevance of these molecular targets for antidepressant responses.

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Acknowledgments

ALSR and RBL are recipients of CNPq Research Productivity Fellowship. The authors would like to thank the Multiuser Laboratory for Biological Studies (LAMEB), UFSC, for the support.

Funding

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) #449436/2014-4, #310113/2017-2, and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES).

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Authors and Affiliations

  1. Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Priscila B. Rosa, Luis E. B. Bettio, Vivian B. Neis, Morgana Moretti, Isabel Werle, Rodrigo B. Leal & Ana Lúcia S. Rodrigues

  2. Division of Medical Sciences, University of Victoria, Victoria, BC, Canada

    Luis E. B. Bettio

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Correspondence to Ana Lúcia S. Rodrigues.

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All experiments were performed in accordance with the Guidelines of Ethic Committee on Animal Use of the Federal University of Santa Catarina (CEUA/UFSC) the guidelines laid down by the NIH (NIH Guide for the Care and Use of Laboratory Animals) in the USA. The CEUA/UFSC has approved all experimental protocols (approval numbers 00795 and 7485180518).

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Rosa, P.B., Bettio, L.E.B., Neis, V.B. et al. The antidepressant-like effect of guanosine is dependent on GSK-3β inhibition and activation of MAPK/ERK and Nrf2/heme oxygenase-1 signaling pathways. Purinergic Signalling 15, 491–504 (2019). https://doi.org/10.1007/s11302-019-09681-2

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