Bensadoun J C, Mirochnitchenko O, Inouye M, Aebischer P, Zurn A D
Gene Therapy Center and Division of Surgical Research, Lausanne University Medical School, Switzerland.
Eur J Neurosci. 1998 Oct;10(10):3231-6. doi: 10.1046/j.1460-9568.1998.00345.x.
Normal cellular metabolism produces oxidants which are neutralized within cells by antioxidant enzymes and other antioxidants. An imbalance between oxidants and antioxidants has been postulated to lead to the degeneration of specific populations of neurons in neurodegenerative diseases, e.g. Parkinson's disease. The present study investigates whether overexpression of glutathione peroxidase, the enzyme which metabolizes hydrogen peroxide to water, can prevent or slow down neuronal injury in an animal model of Parkinson's disease. Transgenic mice overexpressing the human glutathione peroxidase gene under the control of the mouse hydroxymethylglutaryl-coenzyme A promoter and genetically matched control mice were injected intracerebroventricularly with the dopaminergic neurotoxin 6-hydroxydopamine. Seven days after injection, the number of tyrosine hydroxylase-positive nigral dopaminergic neurons was decreased by 52.4% and 20.5% in 6-hydroxydopamine-injected control and glutathione peroxidase transgenic mice, respectively. Similarly, 3 days after injection of the neurotoxin, striatal dopamine was decreased by 71.2% and 56.5%, respectively. Overexpression of glutathione peroxidase therefore partially protects dopaminergic neurons against 6-hydroxydopamine-induced toxicity.
正常细胞代谢会产生氧化剂，这些氧化剂在细胞内被抗氧化酶和其他抗氧化剂中和。据推测，氧化剂和抗氧化剂之间的失衡会导致神经退行性疾病（如帕金森病）中特定神经元群体的退化。本研究调查了谷胱甘肽过氧化物酶（一种将过氧化氢代谢为水的酶）的过表达是否能预防或减缓帕金森病动物模型中的神经元损伤。在小鼠羟甲基戊二酰辅酶A启动子的控制下，过表达人类谷胱甘肽过氧化物酶基因的转基因小鼠和基因匹配的对照小鼠经脑室内注射多巴胺能神经毒素6-羟基多巴胺。注射后7天，在注射6-羟基多巴胺的对照小鼠和谷胱甘肽过氧化物酶转基因小鼠中，酪氨酸羟化酶阳性黑质多巴胺能神经元的数量分别减少了52.4%和20.5%。同样，注射神经毒素3天后，纹状体多巴胺分别减少了71.2%和56.5%。因此，谷胱甘肽过氧化物酶的过表达可部分保护多巴胺能神经元免受6-羟基多巴胺诱导的毒性作用。
