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Upregulation of antioxidant thioredoxin by antidepressants fluoxetine and venlafaxine

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Abstract

Rationale

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used drugs for the treatment of depression. Studies have shown that chronic treatment with SSRIs and SNRIs produces a protective effect against oxidative stress. Thioredoxin (Trx) is an antioxidant protein that reverses protein cysteine oxidation and facilitates scavenging reactive oxygen species.

Objectives

The current study is to determine whether the SSRI fluoxetine and the SNRI venlafaxine regulate Trx and protect neuronal cells against protein cysteine oxidation.

Methods

HT22 mouse hippocampal cells were incubated with fluoxetine or venlafaxine for 5 days. Protein levels of Trx, Trx reductase (TrxR), and Trx-interacting protein (Txnip) were measured by immunoblotting analysis. Trx and TrxR activities were analyzed by spectrophotometric method. Protein cysteine sulfenylation was measured by dimedone-conjugation assay, while nitrosylation was measured by biotin-switch assay.

Results

We found that treatment with fluoxetine or venlafaxine for 5 days increased Trx and TrxR protein levels but produced no effect on Txnip protein levels. These treatments also increased Trx and TrxR activities. Although treatment with fluoxetine or venlafaxine alone had no effect on sulfenylated and nitrosylated protein levels, both drugs inhibited H2O2-increased sulfenylated protein levels and nitric oxide donor nitrosoglutathione-increased nitrosylated protein levels. Stress increases risk of depression. We also found that treatment with fluoxetine or venlafaxine for 5 days inhibited stress hormone corticosterone-increased total sulfenylated and nitrosylated protein levels.

Conclusions

Our findings suggest that chronic treatment with antidepressants may upregulate Trx, subsequently inhibiting protein sulfenylation and nitrosylation, which may contribute to the protective effect of antidepressants against oxidative stress. Our findings also indicate that thioredoxin is a potential therapeutic target for the treatment of depression.

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Funding

This work is supported by NARSAD Independent Investigator Grant from Brain and Behavior Research Foundation.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada

    Veni Bharti, Hua Tan, Jaspreet Deol, Zijian Wu & Jun-Feng Wang

  2. Kleysen Institute for Advanced Medicine, Health Sciences Centre, SR436-710 William Avenue, Winnipeg, MB, R3E 0Z3, Canada

    Veni Bharti, Hua Tan, Jaspreet Deol, Zijian Wu & Jun-Feng Wang

  3. Department of Psychiatry, University of Manitoba, Winnipeg, Canada

    Jun-Feng Wang

Authors
  1. Veni Bharti
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  2. Hua Tan
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  3. Jaspreet Deol
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Correspondence to Jun-Feng Wang.

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Bharti, V., Tan, H., Deol, J. et al. Upregulation of antioxidant thioredoxin by antidepressants fluoxetine and venlafaxine. Psychopharmacology 237, 127–136 (2020). https://doi.org/10.1007/s00213-019-05350-9

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  • DOI: https://doi.org/10.1007/s00213-019-05350-9

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