Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, 1010 W Avenue B, Kingsville, TX, 78363, USA.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA.
Mol Neurobiol. 2021 Feb;58(2):490-504. doi: 10.1007/s12035-020-02131-w. Epub 2020 Sep 25.
HIV infection and drugs of abuse induce oxidative stress and redox imbalance, which cause neurodegeneration. The mechanisms by which HIV infection and cocaine consumption affect astrocyte energy metabolism, and how this leads to neurodegenerative dysfunction, remain poorly understood. Presently, we investigated how oxidative injury causes the depletion of energy resources and glutathione synthetase (GSS), which in turn activates 5' AMP-activated protein kinase (AMPK), glycolytic enzymes, and mitochondrial biogenesis, finally resulting in nuclear factor erythroid (NRF) transcription in astrocytes. Both human primary astrocytes incubated with HIV-1 Tat protein in vitro and HIV-inducible Tat (iTat) mice exposed to cocaine showed decreased levels of GSS and increased superoxide dismutase (SOD) levels. These changes, in turn, significantly activated AMPK and raised the concentrations of several glycolytic enzymes, along with oxidative phosphorylation, the mitochondrial biogenesis of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) and mitochondrial transcription factor (TFAM), and Nrf1 and Nrf2 gene transcription and protein expression. Moreover, neurons exposed to HIV-1Tat/cocaine-conditioned media showed reductions in dendritic formation, spine density, and neuroplasticity compared with control neurons. These results suggest that redox inhibition of GSS altered AMPK activation and mitochondrial biogenesis to influence Nrf transcription. These processes are important components of the astrocyte signaling network regulating brain energy metabolism in HIV-positive cocaine users. In conclusion, HIV-1 Tat alters redox inhibition, thus increasing glycolytic metabolic profiles and mitochondrial biogenesis, leading to Nrf transcription, and ultimately impacting astrocyte energy resource and metabolism. Cocaine exacerbated these effects, leading to a worsening of neurodegeneration.
HIV 感染和滥用药物会引起氧化应激和氧化还原失衡，从而导致神经退行性变。HIV 感染和可卡因消耗如何影响星形胶质细胞能量代谢，以及这如何导致神经退行性功能障碍，目前仍知之甚少。目前，我们研究了氧化损伤如何导致能量资源和谷胱甘肽合成酶 (GSS) 的消耗，进而激活 5' AMP 激活的蛋白激酶 (AMPK)、糖酵解酶和线粒体生物发生，最终导致星形胶质细胞中的核因子红细胞 (NRF) 转录。体外孵育 HIV-1 Tat 蛋白的人原代星形胶质细胞和暴露于可卡因的 HIV 诱导型 Tat(iTat) 小鼠均显示 GSS 水平降低和超氧化物歧化酶 (SOD) 水平升高。这些变化反过来显著激活了 AMPK，并提高了几种糖酵解酶、氧化磷酸化、过氧化物酶体增殖物激活受体-γ 共激活因子 (PGC-1α) 和线粒体转录因子 (TFAM) 的线粒体生物发生以及 Nrf1 和 Nrf2 基因转录和蛋白表达的浓度。此外，与对照神经元相比，暴露于 HIV-1Tat/可卡因条件培养基的神经元显示树突形成、棘密度和神经可塑性降低。这些结果表明，GSS 的氧化还原抑制改变了 AMPK 的激活和线粒体生物发生，从而影响 Nrf 转录。这些过程是调节 HIV 阳性可卡因使用者大脑能量代谢的星形胶质细胞信号网络的重要组成部分。总之，HIV-1 Tat 改变了氧化还原抑制，从而增加了糖酵解代谢谱和线粒体生物发生，导致 Nrf 转录，并最终影响星形胶质细胞的能量资源和代谢。可卡因加剧了这些影响，导致神经退行性变恶化。
