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Creatine Prevents Corticosterone-Induced Reduction in Hippocampal Proliferation and Differentiation: Possible Implication for Its Antidepressant Effect

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Abstract

The benefits of creatine supplementation have been reported in a broad range of central nervous system diseases, including depression, although the mechanisms underlying these effects remain to be understood. In the present study, we investigated the ability of creatine to counteract the morphological and behavioral effects elicited by chronic administration of corticosterone (CORT, 20 mg/kg, p.o.) for 21 days to mice, a pharmacological model of depression that mimics exposure to stress. CORT treatment increased immobility time in the tail suspension test (TST) and forced swim test (FST), as well as latency to immobility in the FST, and decreased the sucrose consumption in the sucrose preference test (SPT). These behavioral effects were associated with decreased hippocampal cell proliferation and neuronal differentiation and increased glial fibrillary acid protein (GFAP) immunostaining (suggestive of astrogliosis) in dentate gyrus (DG) of the hippocampus. These CORT-induced alterations were abolished by treatment with either fluoxetine (a conventional antidepressant) or creatine for 21 days (both 10 mg/kg, p.o.). In addition, fluoxetine, but not creatine, was able to reverse the CORT-induced reduction in serum CORT levels. Collectively, our results suggest that creatine produces morphological alterations that contribute to the improvement of depressive-like behaviors triggered by chronic CORT administration in mice.

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Abbreviations

Akt/PKB:

Protein kinase B

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

CaMK-II:

Ca2+/calmodulin-dependent protein kinase II

CORT:

Corticosterone

DAB:

2,2-Diaminobenzidine

DG:

Dentate gyrus

DMSO:

Dimethyl sulfoxide

FST:

Forced swimming test

GFAP:

Glial fibrillary acid protein

HPA:

Hypothalamic–pituitary–adrenal

MEK1/2:

Mitogen-activated protein kinase kinase 1/2

mTOR:

Mammalian target of rapamycin

NeuroD:

Neurogenic differentiation protein

NHS:

Normal horse serum

OFT:

Open field test

p.o.:

Per os (oral route)

PBS:

Phosphate-buffered saline

PBS-Tx:

Phosphate buffer saline-Triton X-100

PI3K:

Phosphatidylinositol-3-kinase

PKA:

Protein kinase A

PKC:

Protein kinase C

S.E.M.:

Standard error of the mean

SCT:

Sucrose consumption test

SGZ:

Subgranular zone

SSRIs:

Selective serotonin reuptake inhibitors

SVZ:

Subventricular zone

TBS:

Tris-buffered saline

TST:

Tail suspension test

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Acknowledgments

J.G.M. and A.L.S.R. acknowledge funding from the Science Without Borders funding program [Programa Ciência Sem Fronteiras/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Project no. 403120/2012-8] of the Brazilian Federal Government. This study was also supported by grants from CNPq (no. 308723/2013-9, no. 449436/2014-4) and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), NENASC Project (PRONEX-FAPESC/CNPq) no. 1262/2012-9. A.L.S.R. is CNPq Research Fellow.

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

    Francis L. Pazini, Mauricio P. Cunha, Dayane Azevedo, Julia M. Rosa, André Colla, Jade de Oliveira, Ana B. Ramos-Hryb & Ana Lúcia S. Rodrigues

  2. Department of Morphological Sciences, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, 88040-900, Brazil

    Patricia S. Brocardo

  3. Division of Medical Sciences and UBC Island Medical Program, University of Victoria, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada

    Joana Gil-Mohapel

Authors
  1. Francis L. Pazini
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  2. Mauricio P. Cunha
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  3. Dayane Azevedo
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  4. Julia M. Rosa
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  5. André Colla
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  6. Jade de Oliveira
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  7. Ana B. Ramos-Hryb
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  8. Patricia S. Brocardo
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  9. Joana Gil-Mohapel
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  10. Ana Lúcia S. Rodrigues
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Corresponding author

Correspondence to Ana Lúcia S. Rodrigues.

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The authors declare that no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holding that could be perceived as constituting a potential conflict of interest.

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Pazini, F.L., Cunha, M.P., Azevedo, D. et al. Creatine Prevents Corticosterone-Induced Reduction in Hippocampal Proliferation and Differentiation: Possible Implication for Its Antidepressant Effect. Mol Neurobiol 54, 6245–6260 (2017). https://doi.org/10.1007/s12035-016-0148-0

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  • DOI: https://doi.org/10.1007/s12035-016-0148-0

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