Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
PLoS One. 2010 Oct 15;5(10):e13427. doi: 10.1371/journal.pone.0013427.
It is becoming widely accepted that psychoactive drugs, often abused by HIV-I infected individuals, can significantly alter the progression of neuropathological changes observed in HIV-associated neurodegenerative diseases (HAND). The underlying mechanisms mediating these effects however, remain poorly understood. In the current study, we explored whether the psychostimulant drug cocaine could exacerbate toxicity mediated by gp120 in rat primary astrocytes. Exposure to both cocaine and gp120 resulted in increased cell toxicity compared to cells treated with either factor alone. The combinatorial toxicity of cocaine and gp120 was accompanied by an increase in caspase-3 activation. In addition, increased apoptosis of astrocytes in the presence of both the agents was associated with a concomitant increase in the production of intracellular reactive oxygen species and loss of mitochondrial membrane potential. Signaling pathways including c-jun N-teminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK), and nuclear factor (NF-κB) were identified to be major players in cocaine and gp120-mediated apoptosis of astrocytes. Our results demonstrated that cocaine-mediated potentiation of gp120 toxicity involved regulation of oxidative stress, mitochondrial membrane potential and MAPK signaling pathways.
人们越来越接受这样一种观点，即精神活性药物（通常被 HIV-I 感染者滥用）可显著改变与 HIV 相关的神经退行性疾病（HAND）中观察到的神经病变变化的进展。然而，介导这些影响的潜在机制仍知之甚少。在当前的研究中，我们探讨了致幻剂可卡因是否会加剧 gp120 在大鼠原代星形胶质细胞中引起的毒性。与单独用任一因子处理的细胞相比，暴露于可卡因和 gp120 两者都会导致细胞毒性增加。可卡因和 gp120 的组合毒性伴随着 caspase-3 激活的增加。此外，在两种药物存在的情况下，星形胶质细胞的凋亡增加与细胞内活性氧的产生增加和线粒体膜电位的丧失同时发生。包括 c-jun N-末端激酶（JNK）、p38、细胞外信号调节激酶（ERK）/丝裂原激活蛋白激酶（MAPK）和核因子（NF-κB）在内的信号通路被确定为可卡因和 gp120 介导星形胶质细胞凋亡的主要参与者。我们的结果表明，可卡因介导的 gp120 毒性增强涉及氧化应激、线粒体膜电位和 MAPK 信号通路的调节。
