McCarthy S, Somayajulu M, Sikorska M, Borowy-Borowski H, Pandey S
Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Toxicol Appl Pharmacol. 2004 Nov 15;201(1):21-31. doi: 10.1016/j.taap.2004.04.019.
Neuronal cell death induced by oxidative stress is correlated with numerous neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. The causes of sporadic forms of age-related neurodegenerative diseases are still unknown. Recently, a correlation between paraquat exposure and neurodegenerative diseases has been observed. Paraquat, a nonselective herbicide, was once widely used in North America and is still routinely used in Taiwan. We have used differentiated Human Neuroblastoma (SHSY-5Y) cells as an in vitro model to study the mechanism of cell death induced by paraquat. We observed that paraquat-induced oxidative stress in differentiated SHSY-5Y cells as indicated by an increase in the production of cellular reactive oxygen species (ROS). Furthermore, apoptosis was evident as indicated by cellular and nuclear morphology and DNA fragmentation. Interestingly, pretreatment of SHSY-5Y cells with water-soluble Coenzyme Q10 (CoQ10) before paraquat exposure inhibited ROS generation. Pretreatment with CoQ10 also significantly reduced the number of apoptotic cells and DNA fragmentation. We also analyzed the effect of paraquat and CoQ10 on isolated mitochondria. Our results indicated that treatment with paraquat induced the generation of ROS from isolated mitochondria and depolarization of the inner mitochondrial membrane. Pretreatment with CoQ10 was able to inhibit ROS generation from isolated mitochondria as well as the collapse of mitochondrial membrane potential. Our results indicate that water-soluble CoQ10 can prevent oxidative stress and neuronal damage induced by paraquat and therefore, can be used for the prevention and therapy of neurodegenerative diseases caused by environmental toxins.
氧化应激诱导的神经元细胞死亡与许多神经退行性疾病相关，包括阿尔茨海默病（AD）、帕金森病（PD）和中风。散发性年龄相关性神经退行性疾病的病因仍不清楚。最近，已观察到百草枯暴露与神经退行性疾病之间存在关联。百草枯是一种非选择性除草剂，曾在北美广泛使用，目前仍在台湾常规使用。我们使用分化的人神经母细胞瘤（SHSY-5Y）细胞作为体外模型，研究百草枯诱导细胞死亡的机制。我们观察到，百草枯诱导分化的SHSY-5Y细胞产生氧化应激，表现为细胞活性氧（ROS）生成增加。此外，细胞和细胞核形态以及DNA片段化表明细胞凋亡明显。有趣的是，在百草枯暴露前用水溶性辅酶Q10（CoQ10）预处理SHSY-5Y细胞可抑制ROS生成。用CoQ10预处理还显著减少了凋亡细胞的数量和DNA片段化。我们还分析了百草枯和CoQ10对分离线粒体的影响。我们的结果表明，用百草枯处理可诱导分离线粒体产生ROS并导致线粒体内膜去极化。用CoQ10预处理能够抑制分离线粒体产生ROS以及线粒体膜电位的崩溃。我们的结果表明，水溶性CoQ10可以预防百草枯诱导的氧化应激和神经元损伤，因此可用于预防和治疗由环境毒素引起的神经退行性疾病。
