McLaughlin Jay P, Paris Jason J, Mintzopoulos Dionyssios, Hymel Kristen A, Kim Jae K, Cirino Thomas J, Gillis Timothy E, Eans Shainnel O, Vitaliano Gordana D, Medina Jessica M, Krapf Richard C, Stacy Heather M, Kaufman Marc J
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610.
Virginia Commonwealth University, Department of Pharmacology & Toxicology, Richmond, VA 23298.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Oct;2(7):599-609. doi: 10.1016/j.bpsc.2017.04.002. Epub 2017 Apr 20.
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.
HIV/AIDS患者中重度抑郁症的患病率显著高于普通人群。这种共病的潜在机制尚不清楚。HIV产生并分泌的HIV转录反式激活因子（Tat）蛋白可能与此有关。我们确定了小鼠体内条件性Tat蛋白表达是否足以诱发抑郁样行为和氧化应激。此外，由于氧化应激与抑郁症有关，我们分别给予甲磺酰甲烷（MSM）或马来酸二乙酯（DEM）来降低或增加氧化应激，以确定其是否会改变抑郁样行为。
GT-tg双基因小鼠腹腔注射生理盐水或强力霉素（Dox，25 - 100 mg/kg/天）以诱导Tat表达。不表达Tat蛋白的G-tg小鼠也接受Dox。通过悬尾试验（TST）和两瓶糖精/水消耗任务评估抑郁样行为。离体评估活性氧/氮物种（ROS/RNS）。使用9.4特斯拉质子磁共振波谱（MRS）在体内测量内侧前额叶皮质（MFC）的氧化应激和温度。
Tat表达以暴露依赖的方式增加TST不动时间并减少糖精消耗。在生理盐水处理的GT-tg小鼠中，MSM减少不动时间，而DEM增加不动时间。Tat和MSM的行为效应持续28天。Tat和DEM增加，而MSM降低ROS/RNS水平。Tat表达增加MFC谷胱甘肽水平和温度。
Tat表达诱发了快速且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，HIV产生的Tat可能导致HIV感染者中抑郁症的高患病率。此外，减轻氧化应激可降低抑郁症的严重程度。
