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Neuroprotective effects of mirtazapine and imipramine and their effect in pro- and anti-apoptotic gene expression in human neuroblastoma cells

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Abstract

Background

Experimental and clinical studies indicate that neuronal death with the presence of high levels of reactive oxygen species are present in depressed patients and antidepressants might display neuroprotective effects against them. However, the mechanisms underlying antidepressant neuroprotection are not completely understood. In our previous study, we showed that mirtazapine modulated the expression of pro- and anti-apoptotic proteins in mouse brain structures, but there are no data in human cells. Thus, this work was designed to study the possible neuroprotective properties of mirtazapine and imipramine, two commercially available antidepressants with different primary mechanisms of action, in human neuroblastoma SH-SY5Y cells against an oxidative insult.

Methods

SH-SY5Y cells were preincubated with mirtazapine and imipramine (1–20 μM) for 24 h, then hydrogen peroxide (H2O2) was added into the medium containing the antidepressants for additional 24 h, and MTT assay was carried out subsequently. Also, to elucidate the molecular mechanism underlying the neuroprotective properties of antidepressants, we investigated the effects of mirtazapine and imipramine (2 μM) in pro- and anti-apoptotic proteins gene expression in SH-SY5Y cells.

Results

Mirtazapine (1 and 2 μM) and imipramine (1and 2 μM) protected against hydrogen peroxide-induced cellular viability impairment. Most importantly, both compounds reduced p53 mRNA expression, but only imipramine enhanced the Bcl-2/Bax ratio.

Conclusions

The obtained data indicate that mirtazapine and imipramine have neuroprotective effects against H2O2-induced cell death. Although both antidepressants reduced Bax and p53 mRNA expression, only the protection mediated by imipramine might be due to its ability to enhance Bcl-2/Bax ratio.

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Abbreviations

5-HT1A :

Serotonin receptor type 1A

Akt:

Protein kinase B

BDNF:

Brain-derived neurotrophic factor

cDNA:

Complementary deoxyribonucleic acid

CREB:

CAMP response element-binding protein

MAPK:

Mitogen-activated protein kinase

LPS:

Lipopolysaccharides

mRNA:

Messenger ribonucleic acid

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Acknowledgements

SH-SY5Y cells were gently donated by Dr. Marcelo Farina from Universidade Federal de Santa Catarina. The article was proofread by Dr. Mauricio Peña Cunha from Universidade Federal de Santa Catarina.

Funding

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), FAPESC (TO 22.333/2010-6). IBN-Net/CNPq (IBN 01.06.0842-00), CAPES-PROCAD, CAPES-REUNI, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES. INCT-National Institute of Science and Technology for Excitotoxicity and Neuroprotection. NHG, ALSR and RBL are recipients of CNPq fellowship. All these institutions are governmental institutions without influence under this work.

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Authors and Affiliations

  1. Departamento de Bioquímica, CCB, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, 88040-900, Brazil

    Vicente Lieberknecht, Daiane Engel, Ana Lúcia S. Rodrigues & Nelson H. Gabilan

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  1. Vicente Lieberknecht
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  2. Daiane Engel
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  3. Ana Lúcia S. Rodrigues
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  4. Nelson H. Gabilan
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Contributions

VL, ALSR and NHG designed the study, wrote the protocol, and wrote the manuscript. VL and DE performed cell culture experiments, VL and DE performed the qRT-PCR analysis. VL statistical analysis. VL, DE, ALSR and NHG managed the literature searches and analysis. All authors contributed and have approved the manuscript.

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Correspondence to Vicente Lieberknecht.

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Lieberknecht, V., Engel, D., Rodrigues, A.L.S. et al. Neuroprotective effects of mirtazapine and imipramine and their effect in pro- and anti-apoptotic gene expression in human neuroblastoma cells. Pharmacol. Rep 72, 563–570 (2020). https://doi.org/10.1007/s43440-019-00009-w

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