Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
Kleysen Institute for Advanced Medicine, Health Sciences Centre, SR436-710 William Avenue, Winnipeg, MB, R3E 0Z3, Canada.
Psychopharmacology (Berl). 2020 Jan;237(1):127-136. doi: 10.1007/s00213-019-05350-9. Epub 2019 Aug 31.
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 HO-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.
选择性 5-羟色胺再摄取抑制剂（SSRIs）和 5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRIs）是治疗抑郁症最常用的药物。研究表明，SSRIs 和 SNRIs 的慢性治疗可产生抗氧化应激的保护作用。硫氧还蛋白（Trx）是一种抗氧化蛋白，可逆转蛋白质半胱氨酸氧化，并促进清除活性氧。
本研究旨在确定 SSRI 氟西汀和 SNRI 文拉法辛是否调节 Trx 并保护神经元细胞免受蛋白质半胱氨酸氧化。
用氟西汀或文拉法辛孵育 HT22 小鼠海马细胞 5 天。用免疫印迹分析测定 Trx、Trx 还原酶（TrxR）和 Trx 相互作用蛋白（Txnip）的蛋白水平。用分光光度法分析 Trx 和 TrxR 活性。用 dimedone 缀合测定法测定蛋白质半胱氨酸亚磺酰化，用生物素转换测定法测定亚硝基化。
我们发现，用氟西汀或文拉法辛处理 5 天可增加 Trx 和 TrxR 蛋白水平，但对 Txnip 蛋白水平没有影响。这些处理还增加了 Trx 和 TrxR 的活性。虽然氟西汀或文拉法辛单独处理对亚磺酰化和亚硝基化蛋白水平没有影响，但这两种药物均抑制 HO-增加的亚磺酰化蛋白水平和一氧化氮供体硝普酸钠增加的亚硝基化蛋白水平。应激增加了患抑郁症的风险。我们还发现，用氟西汀或文拉法辛处理 5 天可抑制应激激素皮质酮增加的总亚磺酰化和亚硝基化蛋白水平。
我们的研究结果表明，慢性使用抗抑郁药可能上调 Trx，随后抑制蛋白质亚磺酰化和亚硝基化，这可能有助于抗抑郁药对抗氧化应激的保护作用。我们的研究结果还表明，硫氧还蛋白是治疗抑郁症的潜在治疗靶点。
