Francesca Isabella De Simone, Nune Darbinian, Shohreh Amini, Madesh Muniswamy, Martyn K White, John W Elrod, Prasun K Datta, Dianne Langford, Kamel Khalili
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引用次数: 0
Abstract
Addictive stimulant drugs, such as cocaine, are known to increase the risk of exposure to HIV-1 infection and hence predispose towards the development of AIDS. Previous findings suggested that the combined effect of chronic cocaine administration and HIV-1 infection enhances cell death. Neuronal survival is highly dependent on the health of mitochondria providing a rationale for assessing mitochondrial integrity and functionality following cocaine treatment, either alone or in combination with the HIV-1 viral protein Tat, by monitoring ATP release and mitochondrial membrane potential (ΔΨm). Our results indicate that exposing human and rat primary hippocampal neurons to cocaine and HIV-1 Tat synergistically decreased both mitochondrial membrane potential and ATP production. Additionally, since previous studies suggested HIV-1 infection alters autophagy in the CNS, we investigated how HIV-1 Tat and cocaine affect autophagy in neurons. The results indicated that Tat induces an increase in LC3-II levels and the formation of Parkin-ring-like structures surrounding damaged mitochondria, indicating the possible involvement of the Parkin/PINK1/DJ-1 (PPD) complex in neuronal degeneration. The importance of mitochondrial damage is also indicated by reductions in mitochondrial membrane potential and ATP content induced by HIV-1 Tat and cocaine.
众所周知,可卡因等成瘾性兴奋剂会增加感染 HIV-1 病毒的风险,从而诱发艾滋病。以前的研究结果表明,长期服用可卡因和感染 HIV-1 病毒共同作用会加剧细胞死亡。神经元的存活高度依赖于线粒体的健康,这为通过监测 ATP 释放和线粒体膜电位(ΔΨm)来评估线粒体的完整性和功能性提供了理由。我们的研究结果表明,将人和大鼠原代海马神经元置于可卡因和 HIV-1 Tat 的作用下会协同降低线粒体膜电位和 ATP 的产生。此外,由于之前的研究表明 HIV-1 感染会改变中枢神经系统的自噬,我们研究了 HIV-1 Tat 和可卡因如何影响神经元的自噬。结果表明,Tat 会诱导 LC3-II 水平的升高,并在受损线粒体周围形成 Parkin 环状结构,这表明 Parkin/PINK1/DJ-1 (PPD) 复合物可能参与了神经元变性。HIV-1 Tat 和可卡因引起的线粒体膜电位和 ATP 含量降低也表明了线粒体损伤的重要性。
期刊介绍:
The aims of the Journal of Neuroimmune Pharmacology are to promote the dissemination, interest, and exchange of new and important discoveries for the pharmacology and immunology of the nervous system. The aims parallel that of the Society on NeuroImmune Pharmacology by increasing the fundamental understanding of neurologic and neuropsychiatric disorders affected by the immune system or vice versa and towards pharmacologic measures that lead, either to a better understanding of disease mechanisms, or by improving disease outcomes. The scope of JNIP includes all primary works and reviews into the etiology, prevention, and treatment of neuroimmune and nervous system diseases affected by disordered immunity. Original studies serving to define neuroimmune modulation of environmental or endogenous cues such as toxins and drugs of abuse, hormones, and cytokines are welcome. JNIP will serve as a reliable source of interdisciplinary information bridging the fields of pharmacology, immunology, and neuroscience.