Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress.
Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress.
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DOI：
10.1016/j.bpsc.2017.04.002
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Kaufman MJ
中科院分区：
文献类型：
--
作者：
McLaughlin JP;Paris JJ;Mintzopoulos D;Hymel KA;Kim JK;Cirino TJ;Gillis TE;Eans SO;Vitaliano GD;Medina JM;Krapf RC;Stacy HM;Kaufman MJ
在艾滋病毒/艾滋病患者中，重度抑郁症的患病率明显高于一般人群。这种合并症的机制尚不清楚。HIV转录反激活因子（Tat）蛋白，由HIV产生和排泄，可能参与其中。我们确定条件Tat蛋白在小鼠中的表达是否足以诱导抑郁样行为和氧化应激。此外，由于氧化应激与抑郁症有关，我们确定分别通过给予甲基磺酰甲烷（MSM）或马来酸二乙酯（DEM）来减少或增加氧化应激是否会改变抑郁样行为。GT-tg基因小鼠腹腔注射生理盐水或强力霉素（Dox, 25-100 mg/kg/day）诱导Tat表达。不表达Tat蛋白的G-tg小鼠也接受Dox。抑郁样行为通过悬尾试验（TST）和两瓶糖精/水消耗任务进行评估。体外评估活性氧/氮种（ROS/RNS）。采用9.4特斯拉质子磁共振波谱法（MRS）测定体内内侧额叶皮层（MFC）氧化应激和温度。这种表达以暴露依赖的方式增加了TST不动时间，并减少了糖精的消耗。在盐水处理的GT-tg小鼠中，MSM减少静止时间，而DEM增加静止时间。Tat和MSM的行为影响持续了28天。Tat和DEM升高，而MSM降低ROS/RNS水平。Tat的表达增加了MFC谷胱甘肽水平和温度。这种表达诱导了快速和持久的抑郁样行为和氧化应激。增加/减少氧化应激分别增加/减少抑郁样行为。因此，艾滋病毒产生的Tat可能是导致艾滋病毒感染者抑郁患病率高的原因。此外，减轻氧化应激可以减轻抑郁症的严重程度。
The prevalence of major depression in those with HIV/AIDS is substantially higher than in the general population. Mechanisms underlying this comorbidity are poorly understood. HIV-transactivator of transcription (Tat) protein, produced and excreted by HIV, could be involved. We determined whether conditional Tat protein expression in mice is sufficient to induce depression-like behaviors and oxidative stress. Further, as oxidative stress is associated with depression, we determined whether decreasing or increasing oxidative stress by administering methylsulfonylmethane (MSM) or diethylmaleate (DEM), respectively, altered depression-like behavior. GT-tg bigenic mice received intraperitoneal saline or doxycycline (Dox, 25–100 mg/kg/day) to induce Tat expression. G-tg mice, which do not express Tat protein, also received Dox. Depression-like behavior was assessed with the tail suspension test (TST) and the two-bottle saccharin/water consumption task. Reactive oxygen/nitrogen species (ROS/RNS) were assessed ex vivo. Medial frontal cortex (MFC) oxidative stress and temperature were measured in vivo with 9.4-Tesla proton magnetic resonance spectroscopy (MRS). Tat expression increased TST immobility time in an exposure-dependent manner and reduced saccharin consumption. MSM decreased immobility time while DEM increased it in saline-treated GT-tg mice. Tat and MSM behavioral effects persisted for 28 days. Tat and DEM increased while MSM decreased ROS/RNS levels. Tat expression increased MFC glutathione levels and temperature. Tat expression induced rapid and enduring depression-like behaviors and oxidative stress. Increasing/decreasing oxidative stress increased/decreased, respectively, depression-like behavior. Thus, Tat produced by HIV may contribute to the high depression prevalence among those with HIV. Further, mitigation of oxidative stress could reduce depression severity.
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