Acute phencyclidine neurotoxicity in rat forebrain: induction of haem oxygenase-1 and attenuation by the antioxidant dimethylthiourea |
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Authors: | Sunita Rajdev rew S Fix Frank R Sharp |
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Institution: | Department of Neurology, University of California, San Francisco, CA 94143, USA, Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA, and;Procter &Gamble Miami Valley Laboratories, Cincinnati, OH 45011, USA |
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Abstract: | 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. |
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Keywords: | dopamine haem oxygenase heat shock proteins neurodegeneration NMDA receptor antagonists oxidative stress schizophrenia stress proteins |
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