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Ursolic acid abrogates depressive-like behavior and hippocampal pro-apoptotic imbalance induced by chronic unpredictable stress

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Abstract

Emerging evidence has shown that ursolic acid exerts antidepressant-like effects, however, its ability to elicit an antidepressant-like response in rodents subjected to stress model that mimics behavioral and neurochemical alterations found in depression remains to be determined. Thus, this study investigated the possible antidepressant-like effect of ursolic acid in mice subjected to chronic unpredictable stress (CUS) for 14 days, and whether this effect could be associated with the modulation of serum corticosterone levels and hippocampal Bcl-2/Bax mRNA expression. Our results indicated that CUS induced a depressive-like behavior, as demonstrated by an increase in the immobility time and latency to first grooming in the tail suspension test and splash test, respectively. Conversely, the repeated administration of ursolic acid (0.1 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) in the last 7 days of CUS completely prevented CUS-induced behavioral alterations, suggesting an antidepressant-like effect. Additionally, CUS significantly increased the mRNA expression of Bax (pro-apoptosis marker), but not Bcl-2 (anti-apoptosis marker) in the hippocampus. Moreover, reduced hippocampal mRNA expression of Bcl-2/Bax ratio was detected in CUS-exposed mice. Ursolic acid, but not fluoxetine, prevented CUS-induced increase in the expression of Bax, but both ursolic acid and fluoxetine prevented CUS-induced reduction on Bcl-2/Bax ratio. Furthermore, neither CUS nor treatments with ursolic acid or fluoxetine altered serum corticosterone levels. Our study unveils the ability of ursolic acid to prevent the depressive-like behavior induced by stress and the modulation of Bcl-2/Bax expression could be associated with this response.

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Acknowledgements

The authors thank funding agencies CNPq and CAPES by the financial support, and the Laboratório Multiusuário de Estudos em Biologia (LAMEB) by technical support.

Funding

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #310113/2017-2 and #150082/2018-5), and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES). ALSR is a CNPq Research Fellow.

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Authors and Affiliations

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

    André R. S. Colla, Francis L. Pazini, Vicente Lieberknecht, Anderson Camargo & Ana Lúcia S. Rodrigues

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  1. André R. S. Colla
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  2. Francis L. Pazini
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  3. Vicente Lieberknecht
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  4. Anderson Camargo
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  5. Ana Lúcia S. Rodrigues
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Contributions

Ana Lúcia S. Rodrigues and André R.S. Colla designed the study and wrote the protocol. André R.S. Colla, Francis L. Pazini, Vicente Lieberknecht, and Anderson Camargo performed the behavioral and biochemical tests and undertook the statistical analysis. All authors wrote the first draft of the manuscript, as well as approved the final manuscript.

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Correspondence to Ana Lúcia S. Rodrigues.

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All procedures were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and the protocols were approved by the Institutional Ethics Committee.

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Colla, A.R.S., Pazini, F.L., Lieberknecht, V. et al. Ursolic acid abrogates depressive-like behavior and hippocampal pro-apoptotic imbalance induced by chronic unpredictable stress. Metab Brain Dis 36, 437–446 (2021). https://doi.org/10.1007/s11011-020-00658-4

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