Rajdev S, Fix A S, Sharp F R
Department of Neurology, University of California, San Francisco 94143, USA.
Eur J Neurosci. 1998 Dec;10(12):3840-52. doi: 10.1046/j.1460-9568.1998.00392.x.
Phencyclidine and other N-methyl-D-aspartate receptor antagonists are toxic to pyramidal neurons in the posterior cingulate/retrosplenial cortex of rat brain. Previous studies have shown induction of heat shock protein 70 in affected neurons. In this study, expression of haem oxygenase-1, a heat shock protein induced by oxidative stress, was examined in rat forebrain after administration of a single intraperitoneal dose of phencyclidine (50 mg/kg). Northern and Western blot analyses of brain tissue extracts from phencyclidine-treated rats revealed a marked induction of haem oxygenase-1 mRNA and protein, respectively. Immunohistochemistry studies revealed that phencyclidine increased haem oxygenase-1 immunoreactivity primarily in posterior cingulate/retrosplenial, piriform and entorhinal cortices, striatum and hippocampus. Haem oxygenase-1 protein was induced in non-neuronal cells, mainly astrocytes. Some microglia expressing haem oxygenase-1 protein were also found in the posterior cingulate/retrosplenial cortex. Haem oxygenase-1 immunoreactive astrocytes and microglia were present in close proximity to the heat shock protein 70-positive neurons in the posterior cingulate/retrosplenial cortex following phencyclidine. Pretreatment of rats with 1,3-dimethylthiourea, an antioxidant, significantly reduced haem oxygenase-1 protein induction by phencyclidine. Thus, induction of haem oxygenase-1 in glia by phencyclidine appears to be mediated mostly by oxidative stress. Experiments with the amino cupric silver stain for neuronal degeneration revealed phencyclidine-induced neurotoxicity in the posterior cingulate/retrosplenial cortex. The number of affected neurons was significantly reduced after 1,3-dimethylthiourea pretreatment. This suggests that the neurotoxicity of N-methyl-D-aspartate antagonists is due in part to the oxidative stress and may be amenable to therapeutic interventions.
苯环利定及其他 N-甲基-D-天冬氨酸受体拮抗剂对大鼠脑内后扣带回/压后皮质的锥体神经元有毒性作用。先前的研究已表明，受影响的神经元中会诱导热休克蛋白 70 的产生。在本研究中，在给大鼠单次腹腔注射苯环利定（50 毫克/千克）后，检测了作为氧化应激诱导产生的一种热休克蛋白的血红素加氧酶-1 在大鼠前脑的表达情况。对苯环利定处理的大鼠脑组织提取物进行的 Northern 印迹和 Western 印迹分析分别显示，血红素加氧酶-1 的 mRNA 和蛋白质有明显的诱导。免疫组织化学研究显示，苯环利定主要在后扣带回/压后皮质、梨状皮质和内嗅皮质、纹状体及海马中增加了血红素加氧酶-1 的免疫反应性。血红素加氧酶-1 蛋白在非神经元细胞中被诱导产生，主要是星形胶质细胞。在后扣带回/压后皮质中也发现了一些表达血红素加氧酶-1 蛋白的小胶质细胞。在苯环利定处理后，后扣带回/压后皮质中血红素加氧酶-1 免疫反应性星形胶质细胞和小胶质细胞紧邻热休克蛋白 70 阳性神经元。用抗氧化剂 1,3-二甲基硫脲对大鼠进行预处理，可显著降低苯环利定诱导的血红素加氧酶-1 蛋白的产生。因此，苯环利定对神经胶质细胞中血红素加氧酶-1 的诱导作用似乎主要是由氧化应激介导的。用氨基铜银染色法检测神经元变性的实验显示，苯环利定在后扣带回/压后皮质中可诱导神经毒性。1,3-二甲基硫脲预处理后，受影响神经元的数量显著减少。这表明 N-甲基-D-天冬氨酸拮抗剂的神经毒性部分归因于氧化应激，并且可能适合进行治疗干预。
