Upregulation of antioxidant thioredoxin by antidepressants fluoxetine and venlafaxine
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.
The current study is to determine whether the SSRI fluoxetine and the SNRI venlafaxine regulate Trx and protect neuronal cells against protein cysteine oxidation.
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.
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.
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.
KeywordsAntidepressants Depression Oxidative stress Thioredoxin Sulfenylation Nitrosylation
This work is supported by NARSAD Independent Investigator Grant from Brain and Behavior Research Foundation.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Blazquez A, Mas S, Plana MT, Gasso P, Mendez I, Torra M, Arnaiz JA, Lafuente A, Lazaro L. (2014) Plasma fluoxetine concentrations and clinical improvement in an adolescent sample diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder. J Clin Psychopharmacol 34:318–326CrossRefGoogle Scholar
- Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, Cianfrogna J, Cox LM, Gibbs JP, Gibbs MA, Hatch H, Hop CE, Kasman IN, Laperle J, Liu J, Liu X, Logman M, Maclin D, Nedza FM, Nelson F, Olson E, Rahematpura S, Raunig D, Rogers S, Schmidt K, Spracklin DK, Szewc M, Troutman M, Tseng E, Tu M, Van Deusen JW, Venkatakrishnan K, Walens G, Wang EQ, Wong D, Yasgar AS, Zhang C (2005) The impact of p-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the Mdr1a/1b knockout mouse model. Drug Metab Dispos 33:165–174CrossRefGoogle Scholar
- García-Rojo G, Fresno C, Vilches N, Díaz-Véliz G, Mora S, Aguayo F, Pacheco A, Parra-Fiedler N, Parra CS, Rojas PS, Tejos M, Aliaga E, Fiedler JL (2017) The ROCK inhibitor Fasudil prevents chronic restraint stress-induced depressive-like behaviors and dendritic spine loss in rat Hippocampus. Int J Neuropsychopharmacol 20:336–345PubMedGoogle Scholar
- Mendez-David I, Tritschler L, El Ali Z, Damiens M, Pallardy M, David D, Kerdine-Römer S, Gardier A (2015) Nrf2-signaling and BDNF: a new target for the antidepressant-like activity of chronic fluoxetine treatment in a mouse model of anxiety/depression. Neurosci Lett 597:121–126CrossRefGoogle Scholar