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Signaling pathways underlying the antidepressant-like effect of inosine in mice

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Abstract

Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A1 and A2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca2+/calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3β) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) response-binding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 μg/mouse, MEK1/2 inhibitor), KN-62 (1 μg/mouse, CaMKII inhibitor), H-89 (1 μg/mouse, PKA inhibitor), and wortmannin (0.1 μg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a sub-effective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 μg/mouse, GSK-3β inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3β. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.

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Acknowledgements

This study was supported by the National Council for Scientific and Technological Development (CNPq) Brazil (projects #308459/2013-0, #481523/2013-8, #308723/2013-9), National Coordination for the Training and Improvement of Higher Education Personnel (CAPES/MINCyT project #249/14), Santa Catarina State Research Foundation (FAPESC/PRONEX Program—NENASC Project; #1262/2012-9), INCT-National Institute of Science and Technology, and Santa Catarina Program for the Training for Special Education (PROESP/CAPES; #1509/2009). ALSR, MPK, and RBL are recipients of Research Scholarship from CNPq. FMG received a fellowship from CAPES Foundation, Ministry of Education of Brazil. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Tanara V. Peres for the comments that improved the manuscript.

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Authors and Affiliations

  1. Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Filipe Marques Gonçalves, Vivian Binder Neis, Mark William Lopes, Ana Lúcia S. Rodrigues, Manuella P. Kaster & Rodrigo Bainy Leal

  2. Department of Nutrition, Center of Health Science, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Débora Kurrle Rieger

  3. Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Isabella A. Heinrich, Ana Paula Costa, Ana Lúcia S. Rodrigues & Rodrigo Bainy Leal

  4. Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Rodrigo Bainy Leal

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  1. Filipe Marques Gonçalves
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Correspondence to Rodrigo Bainy Leal.

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Filipe Marques Gonçalves declares that he has no conflict of interest.

Vivian Binder Neis declares that she has no conflict of interest.

Débora Kurrle Rieger declares that she has no conflict of interest.

Mark William Lopes declares that he has no conflict of interest.

Isabela A. Heinrich declares that she has no conflict of interest.

Ana Paula Costa declares that she has no conflict of interest.

Ana Lúcia S. Rodrigues declares that she has no conflict of interest.

Manuella P. Kaster declares that she has no conflict of interest.

Rodrigo Bainy Leal declares that he has no conflict of interest.

Ethical approval

The procedures in this study were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and all the experimental protocols were approved by the Institutional Ethics Committee (protocol number PP00772). All efforts were made to minimize animal suffering and to reduce the number of animals used in the experiments.

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Gonçalves, F.M., Neis, V.B., Rieger, D.K. et al. Signaling pathways underlying the antidepressant-like effect of inosine in mice. Purinergic Signalling 13, 203–214 (2017). https://doi.org/10.1007/s11302-016-9551-2

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