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Acute phencyclidine neurotoxicity in rat forebrain: induction of haem oxygenase‐1 and attenuation by the antioxidant dimethylthiourea
Author(s) -
Rajdev Sunita,
Fix Andrew S.,
Sharp Frank R.
Publication year - 1998
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1998.00392.x
Subject(s) - phencyclidine , retrosplenial cortex , chemistry , neurotoxicity , heme oxygenase , hippocampus , forebrain , pharmacology , neuroscience , biochemistry , biology , nmda receptor , receptor , central nervous system , heme , toxicity , organic chemistry , enzyme
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.