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Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects
Neurobiology of Stress ( IF 4.3 ) Pub Date : 2020-01-29 , DOI: 10.1016/j.ynstr.2020.100211
Jason J. Paris , Philippe Liere , Sarah Kim , Fakhri Mahdi , Meagan E. Buchanan , Sara R. Nass , Alaa N. Qrareya , Mohammed F. Salahuddin , Antoine Pianos , Neïké Fernandez , Zia Shariat-Madar , Pamela E. Knapp , Michael Schumacher , Kurt F. Hauser

Pregnane steroids, particularly allopregnanolone (AlloP), are neuroprotective in response to central insult. While unexplored in 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.



中文翻译:

HIV-1 Tat和吗啡会改变孕激素的类固醇生成:生理学上的阿洛培那那龙酮具有抗神经毒性和精神运动作用的保护作用

孕烷类固醇,尤其是去甲肾上腺素(AlloP),对中枢神经损伤有神经保护作用。虽然尚未进行体内研究,AlloP可以针对与人类1型免疫缺陷病毒(HIV-1)相关的神经功能障碍提供保护。HIV-1调节蛋白是转录的反式激活因子(Tat),具有神经毒性,其在小鼠中的表达会增加焦虑症的行为。孕酮可以改善这种效果,但是当阻止5α还原被阻止时则无法改善。鉴于Tat的神经毒性作用涉及线粒体功能障碍,且阿片类药物暴露会使其恶化,我们假设Tat和/或联合吗啡会扰乱小鼠的类固醇生成,促进神经元死亡,而外源的AlloP可以挽救这些作用。与其他神经损伤模型一样,在转基因小鼠中有条件地诱导HIV-1 Tat可以显着增强孕烯醇酮和孕酮的5α还原代谢产物(包括AlloP)的中枢合成,同时降低中央脱氧皮质酮(独立于血浆变化)。吗啡可能通过激活下丘脑-垂体-肾上腺应激轴而显着增加了几种类固醇(包括孕酮,脱氧皮质酮,皮质酮及其代谢物)的脑和血浆浓度。达而不是吗啡在原代脾细胞中引起糖皮质激素抵抗。在神经元中,Tat使线粒体膜电位去极化并增加细胞死亡。AlloP的生理浓度(0.1、1或10 nM)可以逆转这些影响。高浓度的AlloP(100 nM)与吗啡合用具有神经毒性。转基因小鼠中的Tat诱导增强了急性吗啡的精神运动作用,而外源性AlloP(1.0 mg / kg,但不是0.5 mg / kg)可以改善。

更新日期:2020-01-29
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