Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States.
Neuroscience. 2012 Jul 12;214:68-77. doi: 10.1016/j.neuroscience.2012.03.061. Epub 2012 Apr 21.
Caspases are implicated in neuronal death in neurodegenerative and other central nervous system (CNS) diseases. In a rat model of human immunodeficiency virus type 1 (HIV-1) associated neurocognitive disorders (HAND), we previously characterized HIV-1 envelope gp120-induced neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In this model, neuronal apoptosis occurred probably via gp120-induced reactive oxygen species (ROS). Antioxidant gene delivery blunted gp120-related apoptosis. Here, we studied the effect of gp120 on different caspases (3, 6, 8, 9) expression. Caspases production increased in the rat caudate-putamen (CP) 6h after gp120 injection into the same structure. The expression of caspases peaked by 24h. Caspases colocalized mainly with neurons. Prior gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) into the CP before injecting gp120 there reduced levels of gp120-induced caspases, recapitulating the effect of antioxidant enzymes on gp120-induced apoptosis observed by TUNEL. Thus, HIV-1 gp120 increased caspases expression in the CP. Prior antioxidant enzyme treatment mitigated production of these caspases, probably by reducing ROS levels.
Caspases 参与神经退行性疾病和其他中枢神经系统 (CNS) 疾病中的神经元死亡。在人类免疫缺陷病毒 1 (HIV-1) 相关神经认知障碍 (HAND) 的大鼠模型中，我们之前通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记 (TUNEL) 测定法描述了 HIV-1 包膜 gp120 诱导的神经元细胞凋亡。在该模型中，神经元细胞凋亡可能是通过 gp120 诱导的活性氧 (ROS) 发生的。抗氧化基因传递减轻了 gp120 相关的细胞凋亡。在这里，我们研究了 gp120 对不同半胱天冬酶 (3、6、8、9) 表达的影响。gp120 注射到相同结构后 6 小时，大鼠尾壳核 (CP) 中的半胱天冬酶产生增加。半胱天冬酶的表达在 24 小时达到峰值。半胱天冬酶主要与神经元共定位。在向 CP 中注射 gp120 之前，将抗氧化酶铜/锌超氧化物歧化酶 (SOD1) 或谷胱甘肽过氧化物酶 (GPx1) 的抗氧化基因传递到 CP 中，可以降低 gp120 诱导的半胱天冬酶的水平，这再现了 TUNEL 观察到的抗氧化酶对 gp120 诱导的凋亡的影响。因此，HIV-1 gp120 增加了 CP 中的半胱天冬酶表达。先前的抗氧化酶处理减轻了这些半胱天冬酶的产生，可能是通过降低 ROS 水平。
