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首页> 外文期刊>Neurobiology of Stress >Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects
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Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects

机译：妊娠甾体制化由HIV-1 TAT和吗啡改变：生理allopregheanolone对神经毒性和精神运动效应保护

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Pregnane steroids, particularly allopregnanolone (AlloP), are neuroprotective in response to central insult. While unexploredin vivo, AlloP may confer protection against the neurological dysfunction associated with human immunodeficiency virus type 1 (HIV-1). The HIV-1 regulatory protein, trans-activator of transcription (Tat), is neurotoxic and its expression in mice increases anxiety-like behavior; an effect that can be ameliorated by progesterone, but not when 5α-reduction is blocked. Given that Tat's neurotoxic effects involve mitochondrial dysfunction and can be worsened with opioid exposure, we hypothesized that Tat and/or combined morphine would perturb steroidogenesis in mice, promoting neuronal death, and that exogenous AlloP would rescue these effects. Like other models of neural injury, conditionally inducing HIV-1 Tat in transgenic mice significantly increased the central synthesis of pregnenolone and progesterone's 5α-reduced metabolites, including AlloP, while decreasing central deoxycorticosterone (independent of changes in plasma). Morphine significantly increased brain and plasma concentrations of several steroids (including progesterone, deoxycorticosterone, corticosterone, and their metabolites) likely via activation of the hypothalamic-pituitary-adrenal stress axis. Tat, but not morphine, caused glucocorticoid resistance in primary splenocytes. In neurons, Tat depolarized mitochondrial membrane potential and increased cell death. Physiological concentrations of AlloP (0.1, 1, or 10?nM) reversed these effects. High-concentration AlloP (100?nM) was neurotoxic in combination with morphine. Tat induction in transgenic mice potentiated the psychomotor effects of acute morphine, while exogenous AlloP (1.0?mg/kg, but not 0.5?mg/kg) was ameliorative. Data demonstrate that steroidogenesis is altered by HIV-1 Tat or morphine and that physiological AlloP attenuates resulting neurotoxic and psychomotor effects.
机译：妊娠类固醇，特别是allopregheanolone（Allop），是对中央侮辱的神经保护性。虽然未开发的体内，Allop可以赋予免受人免疫缺陷病毒类型1（HIV-1）相关的神经功能功能障碍的保护。 HIV-1调节蛋白，转录（TAT）的转移剂是神经毒性，其在小鼠中的表达增加了焦虑状行为;孕酮可以改善的效果，但在5α减少被阻断时没有。鉴于TAT的神经毒性效应涉及线粒体功能障碍，并且可以用阿片样物体暴露恶化，我们假设TAT和/或组合的吗啡会使小鼠扰动类别，促进神经元死亡，并且外源Allop将拯救这些效果。与其他模型的神经损伤一样，有条件地诱导转基因小鼠的HIV-1 TAT显着增加了孕蛋白和孕酮的5α降低的代谢物的中央合成，包括ALLOP，同时降低中枢性脱氧细胞（独立于血浆的变化）。吗啡显着增加了几种类固醇的脑和血浆浓度（包括孕酮，脱氧糖酮，皮质酮和它们的代谢物）可能通过激活下丘脑 - 垂体肾上腺胁迫轴来激活。 TAT，但不是吗啡，导致原发性脾细胞的糖皮质激素抗性。在神经元中，TAT去极化线粒体膜电位和增加的细胞死亡。 Allop的生理浓度（0.1,1或10？nm）反转这些效果。高浓度Allop（100？NM）与吗啡组合是神经毒性。转基因小鼠的Tat诱导调节了急性吗啡的精神疗法作用，而外源Allop（1.0？mg / kg，但不是0.5？mg / kg）。数据表明，通过HIV-1 TAT或吗啡改变甾体化，并且生理ALLOP衰减导致神经毒性和精神疗法的影响。

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