Wang Hui, Cheng Elise, Brooke Sheila, Chang Pearl, Sapolsky Robert
Department of Biological Sciences, and Neurology and Neurological Sciences, Stanford University, Gilbert Laboratory, Stanford, California 94305, USA.
J Neurochem. 2003 Dec;87(6):1527-34. doi: 10.1046/j.1471-4159.2003.02123.x.
There is now considerable knowledge concerning neuron death following necrotic insults, and it is believed that the generation of reactive oxygen species (ROS) and oxidative damage play a pivotal role in the neuron death. Prompted by this, we have generated herpes simplex virus-1 amplicon vectors over-expressing the genes for the antioxidant enzymes catalase (CAT) or glutathione peroxidase (GPX), both of which catalyze the degradation of hydrogen peroxide. Over-expression of each of these genes in primary hippocampal or cortical cultures resulted in increased enzymatic activity of the cognate protein. Moreover, each enzyme potently decreased the neurotoxicity induced by kainic acid, glutamate, sodium cyanide and oxygen/glucose deprivation. Finally, these protective effects were accompanied by parallel decreases in hydrogen peroxide accumulation and the extent of lipid peroxidation. These studies not only underline the key role played by ROS in the neurotoxicity of necrotic insults, but also suggest potential gene therapy approaches.
目前，关于坏死性损伤后神经元死亡已有相当多的知识，并且人们认为活性氧（ROS）的产生和氧化损伤在神经元死亡中起关键作用。受此启发，我们构建了单纯疱疹病毒1型扩增载体，其过度表达抗氧化酶过氧化氢酶（CAT）或谷胱甘肽过氧化物酶（GPX）的基因，这两种酶都催化过氧化氢的降解。在原代海马或皮质培养物中过度表达这些基因中的每一个都会导致同源蛋白的酶活性增加。此外，每种酶都能有效降低由海藻酸、谷氨酸、氰化钠和氧/葡萄糖剥夺诱导的神经毒性。最后，这些保护作用伴随着过氧化氢积累和脂质过氧化程度的平行降低。这些研究不仅强调了ROS在坏死性损伤神经毒性中所起的关键作用，还提出了潜在的基因治疗方法。
