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Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effect of Creatine

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Abstract

Creatine has been proposed to exert beneficial effects in the management of depression, but the cell signaling pathways implicated in its antidepressant effects are not well established. This study investigated the involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. The acute treatment of mice with creatine (1 mg/kg, po) increased the Akt and P70S6K phosphorylation, and HO-1, GPx and PSD95 immunocontents. The pretreatment of mice with LY294002 (10 nmol/mouse, icv, PI3K inhibitor), wortmannin (0.1 μg/mouse, icv, PI3K inhibitor), ZnPP (10 μg/mouse, icv, HO-1 inhibitor), or rapamycin (0.2 nmol/mouse, icv, mTOR inhibitor) prevented the antidepressant-like effect of creatine (1 mg/kg, po) in the TST. In addition, the administration of subeffective dose of either the selective GSK3 inhibitor AR-A014418 (0.01 μg/mouse, icv), the nonselective GSK3 inhibitor lithium chloride (10 mg/kg, po), or the HO-1 inductor CoPP (0.01 μg/mouse, icv), in combination with a subeffective dose of creatine (0.01 mg/kg, po) reduced the immobility time in the TST as compared with either drug alone. No treatment caused significant changes in the locomotor activity of mice. These results indicate that the antidepressant-like effect of creatine in the TST depends on the activation of Akt, Nrf2/HO-1, GPx, and mTOR, and GSK3 inhibition.

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Abbreviations

ARA014418:

N-(4-Methoxybenzyl)-N’-(5-nitro-1,3-thiazol-2-yl)urea

ARE:

Antioxidant response element

CoPP:

Protoporphyrin IX cobalt chloride

ERK 1/2:

Extracellular-signal-regulated kinases 1/2

DMSO:

Dimethyl sulfoxide

GPx:

Glutathione peroxidase

GSK3:

Glycogen synthase kinase-3

HO-1:

Heme oxygenase-1

icv :

Intracerebroventricular

mTOR:

Mammalian target of rapamycin

NMDA:

N-Methyl-D-aspartate

Nrf2:

Nuclear factor-erythroid-derived 2-related factor-2

PI3K:

Phosphatidylinositol 3-kinase

PKA:

cAMP-dependent protein kinase

PKC:

Protein kinase C

po :

per os

Rapamycin:

23,27-epoxy-3H-pyrido[2,1c][1,4] oxaazacyclohentriacontine solution

TST:

Tail suspension test

LY294002:

2-(4-Morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride

ZnPP:

Protoporphyrin IX zinc(II)

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Acknowledgments

This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; #308723/2013-9), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), Rede Instituto Brasileiro de Neurociência (IBN-Net/CNPq; #01.06.0842-00), Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC) Project/PRONEX Program (CNPq/FAPESC; #1262/2012-9). Funding for this study had no further role in study design in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

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

    Mauricio P. Cunha, Josiane Budni, Fabiana K. Ludka, Francis L. Pazini, Julia Macedo Rosa, Ágatha Oliveira, Mark W. Lopes, Carla I. Tasca, Rodrigo B. Leal & Ana Lúcia S. Rodrigues

  2. Center for Health Sciences, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil

    Josiane Budni

  3. Department of Pharmacy, Universidade do Contestado, Canoinhas, SC, Brazil

    Fabiana K. Ludka

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  1. Mauricio P. Cunha
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  2. Josiane Budni
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  4. Francis L. Pazini
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Correspondence to Mauricio P. Cunha.

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Cunha, M.P., Budni, J., Ludka, F.K. et al. Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effect of Creatine. Mol Neurobiol 53, 2954–2968 (2016). https://doi.org/10.1007/s12035-015-9192-4

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